WO2024254091A1 - Traitement de maladies et de troubles liés au fgg - Google Patents

Traitement de maladies et de troubles liés au fgg Download PDF

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Publication number
WO2024254091A1
WO2024254091A1 PCT/US2024/032448 US2024032448W WO2024254091A1 WO 2024254091 A1 WO2024254091 A1 WO 2024254091A1 US 2024032448 W US2024032448 W US 2024032448W WO 2024254091 A1 WO2024254091 A1 WO 2024254091A1
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Prior art keywords
sequence
antisense strand
nucleoside
sense strand
modified
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Inventor
Omri GOTTESMAN
Shannon BRUSE
Paul BUSKE
Eric BUSS
Brian CAJES
David Lewis
David Rozema
John VEKICH
Darren H. Wakefield
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Empirico Inc
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Empirico Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate

Definitions

  • compositions comprising an oligonucleotide that targets fibrinogen gamma gene (FGG).
  • FGG fibrinogen gamma gene
  • compositions comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a mental disorder measurement of a mental disorder.
  • the mental disorder comprises a psychiatric disorder.
  • the psychiatric disorder comprises a depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression and signs or symptoms of depression), post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or schizoaffective disorder.
  • the mental disorder measurement is chosen from the group consisting of a Montgomery-Asberg Depression Rating Scale (MADRS) score, a Hamilton Depression Rating Scale-17 score, anxiety signs and symptoms, eating disorder signs and symptoms, substance-use disorder signs and symptoms, post-traumatic stress disorder signs and symptoms, bipolar disorder signs and symptoms, schizophrenia signs and symptoms, and psychosis signs and symptoms.
  • the mental disorder comprises a neurological disorder.
  • the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache (e.g., migraine), chronic pain (e.g., fibromyalgia), chronic fatigue syndrome (e.g., myalgic encephalomyelitis), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis).
  • Alzheimer’s disease dementia, delirium, cognitive decline, vascular dementia, headache (e.g., migraine), chronic pain (e.g., fibromyalgia), chronic fatigue syndrome (e.g., myalgic encephalomyelitis), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis).
  • the mental disorder measurement is chosen from the group consisting of cognitive function, central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal Attorney Docket No.54462-754.601 fluid (CSF) or plasma beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), Lewy bodies, or alpha-synuclein, headache symptoms or signs, migraine symptoms or signs, chronic pain symptoms or signs, fibromyalgia symptoms or signs, chronic fatigue syndrome (e.g., myalgic encephalomyelitis) symptoms or signs, and motor neuron disease (e.g., amyotrophic lateral sclerosis) symptoms or signs.
  • CNS central nervous system
  • CSF cerebrospinal Attorney Docket No.54462-754.601 fluid
  • beta-amyloid 42 beta-amyloid 40
  • the oligonucleotide comprises a modified internucleoside linkage.
  • the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.
  • the oligonucleotide comprises a modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2’-C-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.
  • the modified nucleoside comprises a LNA.
  • the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid.
  • the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'-deoxyfluoro nucleoside, 2'- O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'-ara-F, or a combination thereof.
  • the modified nucleoside comprises one or more 2’-fluoro modified nucleosides.
  • the modified nucleoside comprises a 2’-O-alkyl modified nucleoside.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.
  • the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or ⁇ - tocopherol, or a combination thereof.
  • the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar comprises N- acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.
  • the sugar moiety may comprise ETL17.
  • the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • the sense strand is 12-30 nucleosides in length.
  • the antisense strand is 12-30 nucleosides in length.
  • compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3621.
  • any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, Attorney Docket No.54462-754.601 and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2
  • the sense strand comprises any one of modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S.
  • any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidine
  • the antisense strand comprises any one of modification patterns 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-1742 or 3713-3748, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1743-3484 or 3749-3784, or a sequence thereof having 1 or 2 substitutions, additions, or deletions.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-1742 or 3713-3748, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 1743-3484 or 3749-3784.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3759, 3760, 3762, or 3783, or a sequence thereof having 1 or 2 substitutions, additions, or deletions.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3759, 3760, 3762, or 3783.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 352, 1003, 1011, or 1278, or a sequence thereof having 1 or 2 substitutions, additions, or deletions; and the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or a sequence thereof having 1 or 2 substitutions, additions, or deletions.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 352, 1003, 1011, or 1278
  • the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3591-3594, or a sequence thereof having 1 or 2 substitutions, additions, or deletions
  • the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3595-3598, or a sequence thereof having 1 or 2 substitutions, additions, or deletions.
  • the sense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3591- 3594
  • the antisense strand comprises the nucleic acid sequence of any one of SEQ ID NOs: 3595- 3598.
  • the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO is 12-30 nucleosides in length.
  • compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 3621.
  • Some embodiments include a pharmaceutically acceptable carrier.
  • methods of treating a subject having a psychiatric disorder or a neurological disorder comprising administering an effective amount of the composition to the subject.
  • the psychiatric disorder comprises a depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression and signs or symptoms of depression), post-traumatic stress disorder, mood disorder, anxiety disorders, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or a schizoaffective disorder.
  • the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache (e.g., migraine), chronic pain (e.g., fibromyalgia), chronic fatigue syndrome (e.g., myalgic encephalomyelitis), chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease (e.g., amyotrophic lateral sclerosis).
  • compositions comprising an oligonucleotide that targets FGG.
  • FGG oligonucleotide that targets FGG.
  • some embodiments may include inhibiting or targeting a FGG protein or FGG RNA.
  • the FGG protein may be inhibited or targeted as a result of there being less production of the FGG protein by translation of the FGG RNA; or a FGG protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a FGG RNA and reduces production of the FGG protein from the FGG RNA.
  • targeting FGG may refer to binding a FGG RNA and reducing FGG RNA or protein levels.
  • the oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).
  • siRNA small interfering RNA
  • ASO antisense oligonucleotide
  • Administration of the oligonucleotide to a subject may improve psychiatric related traits, such as Montgomery-Asberg Depression Rating Scale (MADRS) (e.g., scale ranges from 0 to 60 with a higher score indicating worsening symptoms of depression), Hamilton Depression Rating Scale-17 (e.g., scale ranges from 0 to 52 with a higher score indicating worsening symptoms of depression), anxiety Attorney Docket No.54462-754.601 symptoms and signs, eating disorder symptoms and signs, substance-use disorder symptoms and signs, post-traumatic stress disorder symptoms and signs, bipolar disorder symptoms and signs, schizophrenia symptoms and signs, or psychosis symptoms and signs.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • HVS Hamilton Depression Rating Scale-17
  • anxiety Attorney Docket No.54462-754.601 symptoms and signs eating disorder symptoms and signs, substance-use disorder symptoms and signs, post-traumatic stress disorder symptoms and signs, bipolar disorder symptoms and signs, schizophrenia symptoms and signs, or psychosis symptoms and signs.
  • administration of the oligonucleotide to a subject may improve neurological related traits, such as Cognitive function, central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) or plasma beta- amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein, headache symptoms and signs, migraine symptoms and signs, chronic pain symptoms and signs, fibromyalgia symptoms and signs, chronic fatigue syndrome (ME) symptoms and signs, or motor neuron disease (e.g., ALS) symptoms or signs.
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • beta-amyloid 40 the ratio of beta-amyloid 42 to beta-amyloid 40
  • tau tau
  • phospho-tau neurofilament light chain
  • GFAP
  • a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves a mental disorder measurement in the subject, relative to a baseline mental disorder measurement.
  • the mental disorder comprises a psychiatric disorder.
  • the psychiatric disorder comprises a depressive disorder, post-traumatic stress disorder, mood disorder, anxiety disorder, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or schizoaffective disorder.
  • the mental disorder measurement comprises a Montgomery-Asberg Depression Rating Scale score, a Hamilton Depression Rating Scale score, or a measurement of an anxiety disorder, depressive disorder, eating disorder, substance-use disorder, post-traumatic stress disorder, bipolar disorder, schizophrenia, or psychosis sign or symptom.
  • the mental disorder comprises a neurological disorder.
  • the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease.
  • the mental disorder measurement comprises a measurement of cognitive function, amyloid plaques, tau accumulation, beta-amyloid 42, beta-amyloid 40, the ratio of beta-amyloid 42 to beta-amyloid 40, tau, phospho-tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Lewy bodies, or alpha-synuclein, or a sign or symptom of headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome, or motor neuron disease.
  • a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen.
  • the composition decreases circulating fibrinogen.
  • the subject has a clotting or coagulation disorder.
  • the subject has a thrombophilia.
  • the subject has a venous thromboembolism.
  • the composition further comprises an oligonucleotide that comprises a modified internucleoside linkage.
  • the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • the oligonucleotide Attorney Docket No.54462-754.601 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.
  • the oligonucleotide comprises a modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2’-O-allyl, 2’-C- allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.
  • the modified nucleoside comprises a LNA.
  • the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid.
  • the modified nucleoside comprises 2'-O-methyl nucleoside, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl’(2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.
  • the modified nucleoside comprises one or more 2’-fluoro modified nucleosides.
  • the modified nucleoside comprises 2’-O-alkyl modified nucleoside.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides.
  • the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.
  • the sugar comprises GalNAc.
  • the sugar moiety comprises ETL17.
  • the composition comprises an oligonucleotide that comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • siRNA small interfering RNA
  • the sense strand is 12- 30 nucleosides in length.
  • the antisense strand is 12-30 nucleosides in length.
  • composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 3690.
  • any one of the following is true with regard to the sense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise 2’-O-methyl modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines,
  • the antisense strand comprises a mixture of 2’-fluoro and 2’-O-methyl modified nucleosides.
  • the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO is 12-30 nucleosides in length.
  • disclosed herein is a composition comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 3621.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • a method of treating a subject having a psychiatric disorder or a neurological disorder comprising administering an effective amount of a composition described herein.
  • the method comprises treating a psychiatric disorder that comprises a depressive disorder, persistent depressive disorder, treatment resistant depression, a sign or symptom of depression, post- traumatic stress disorder, mood disorder, anxiety disorders, eating disorder, substance-use disorder, bipolar disorder, personality disorder, schizophrenia, or a schizoaffective disorder.
  • the neurological disorder comprises Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease.
  • compositions comprising an oligonucleotide that targets fibrinogen gamma chain (FGG) and when administered to a cell decreases expression of FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, and wherein: (i) the sense strand comprises any one of modification patterns 31S to 49S; or (ii) the antisense strand comprises any one of modification patterns 22AS to 41AS.
  • siRNA small interfering RNA
  • the oligonucleotide comprises a sugar moiety attached at a 3’ or 5’ terminus of the oligonucleotide. In some embodiments, the sugar moiety is attached at a 5’ terminus of the sense strand. In some embodiments, the sugar comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose. In some embodiments, the sugar comprises GalNAc. In some embodiments, the sugar moiety comprises ETL17. In some embodiments, the antisense strand is complementary or at least 90% complementary to a portion of SEQ ID NO: 3621.
  • the sense strand and the antisense strand each have 14 to 30 nucleotides.
  • the sense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1-1742.
  • the sense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1-1742, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 1-1742.
  • the antisense strand comprises a nucleoside sequence having at least 85% sequence identity to any one of SEQ ID NOs: 1743-3484.
  • the antisense strand comprises the nucleoside sequence of any one of: SEQ ID NOs: 1743-3484, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 1743-3484.
  • the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleobase sequence of a sense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B.
  • the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, Attorney Docket No.54462-754.601 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B, or a nucleobase sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleobase sequence of an antisense strand in any one of Tables 4-8, 9B, 9C, 18B, 22B, 26B, 31B, 33B, 37B, 42B, 47B, 67B, 79B, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 142, 183, 187, 190B.
  • pharmaceutical compositions comprising a composition described herein, and a pharmaceutically acceptable carrier.
  • the mental or neurological disorder comprises a neurodegenerative disease.
  • the mental or neurological disorder is selected from the group consisting of Alzheimer’s disease, dementia, delirium, cognitive decline, vascular dementia, headache, chronic pain, chronic fatigue syndrome, chronic traumatic encephalopathy, traumatic brain injury, and motor neuron disease.
  • headache comprises migraine.
  • chronic pain comprises fibromyalgia.
  • chronic fatigue syndrome comprises myalgic encephalomyelitis.
  • motor neuron disease comprises amyotrophic lateral sclerosis (ALS).
  • the mental or neurological disorder comprises a psychiatric disorder.
  • the psychiatric disorder is selected from the group consisting of post-traumatic stress disorder, mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders.
  • methods of decreasing fibrinogen or fibrin in a subject’s central nervous system (CNS) comprising administering to the subject an effective amount of an FGG siRNA, thereby decreasing a quantity of fibrinogen or fibrin in the subject’s CNS.
  • the quantity of fibrinogen or fibrin is decreased by at least 10% relative to a baseline quantity, or by at least 10% relative to a control.
  • the FGG siRNA is administered to an area of the subject’s body other than the subject’s head or brain.
  • the quantity of fibrinogen or fibrin comprises a quantity of fibrinogen.
  • the quantity of fibrinogen or fibrin comprises a quantity of fibrin.
  • the CNS comprises a brain.
  • the FGG siRNA is included in a composition described herein.
  • a subject’s blood comprising administering to the subject an effective amount of an FGG siRNA, thereby decreasing a quantity of fibrinogen or fibrin in the subject’s blood.
  • the quantity of fibrinogen or fibrin is decreased by at least 10% relative to a baseline quantity, or by at least 10% relative to a control.
  • the FGG siRNA is administered to an area of the subject’s body other than the subject’s head or brain.
  • the quantity of fibrinogen or fibrin comprises a quantity of fibrinogen.
  • the quantity of fibrinogen or fibrin comprises a quantity of fibrin.
  • the blood comprises plasma.
  • the FGG siRNA is included in a composition described herein.
  • described herein is a method of treating a subject Attorney Docket No.54462-754.601 having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the composition described herein to the subject.
  • the subject has a genotype at risk for developing Alzheimer’s disease or dementia.
  • the subject is a heterozygous or homozygous carrier of APOE4.
  • the subject is a heterozygous or homozygous carrier of FGG rs148685782-G (A108) or FGG rs6063-C (G191).
  • evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia.
  • the subject has a polygenic risk score in the 40 th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.
  • the subject has a polygenic risk score in the 20 th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.
  • calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.
  • methods comprising administering an oligonucleotide that targets FGG and when administered to a subject in an effective amount reduces fibrinogen or fibrin in the subject.
  • the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline.
  • the fibrinogen or fibrin is reduced by at least 5%-90% relative to baseline.
  • one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline.
  • the fibrinogen or fibrin is reduced without significant change to one or more non-fibrinogen or fibrin coagulation measurements.
  • the one or more coagulation measurements comprises von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha-2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin- antithrombin complex (TAT), D-dimer (DD), fibrinogen, prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), or bleeding time assay.
  • the subject has a mental or neurological disorder.
  • FIG.1 is an example of a GalNAc ligand.
  • FIG.2 is an example of a GalNAc ligand.
  • FIG.3 includes a chart showing data from an ELISA (A), and a western blot (B) image.
  • a GWAS Genome Wide Association Study
  • a GWAS generally utilizes genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome.
  • the Attorney Docket No.54462-754.601 most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is considered associated with disease.
  • Association statistics used in a GWAS include p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size.
  • OR odds ratios
  • beta coefficients beta coefficients
  • the choice of therapeutic modality depends on factors such as the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, liver, brain, or neural tissue) and a relevant indication.
  • a target for example, intracellular, extracellular, or secreted
  • a relevant tissue for example, liver, brain, or neural tissue
  • the fibrinogen gamma chain gene also known as fibrinogen gamma gene (FGG)
  • FGG protein may be a gamma component of fibrinogen.
  • FGG protein may include 453 amino acids and have a mass of about 51.5 kDa.
  • An example of a FGG amino acid sequence, and further description of FGG is included at uniprot.org under accession no.
  • FGG may be secreted by the liver cells such as hepatocytes.
  • inhibition of FGG may serve as a therapeutic for treatment of psychiatric diseases and disorders such as depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression, or signs and symptoms of depression), post-traumatic stress disorder (PTSD), mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders, and neurological diseases and disorders such as Alzheimer’s disease, dementia, delirium, Attorney Docket No.54462-754.601 cognitive decline, vascular dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis).
  • depressive disorder e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression, or signs and symptoms of depression
  • PTSD post-traumatic stress disorder
  • mood disorders anxiety disorders
  • eating disorders substance
  • a reduction of liver FGG expression may affect FGG, fibrinogen, or fibrin levels elsewhere in the body.
  • FGG may be expressed in liver cells, secreted into circulation, and accumulate in other tissues or areas of the body such as the central nervous system (CNS) or brain.
  • CNS central nervous system
  • a reduction in FGG mRNA or protein e.g., resultant from treatment with a FGG siRNA
  • may lead to reduced assembly and secretion of fibrinogen by the liver which may then also reduce the amount of fibrinogen or its degradation product, fibrin, that enters other tissues (e.g., that is able to cross the blood brain barrier and be deposited in the CNS or brain).
  • compositions comprising an oligonucleotide.
  • the composition comprises an oligonucleotide that targets FGG.
  • the composition consists of an oligonucleotide that targets FGG.
  • the oligonucleotide reduces FGG mRNA expression in the subject.
  • the oligonucleotide reduces FGG protein expression in the subject.
  • the oligonucleotide may include a small interfering RNA (siRNA) described herein.
  • the oligonucleotide may include an antisense oligonucleotide (ASO) described herein.
  • ASO antisense oligonucleotide
  • a composition described herein is used in a method of treating a disorder in a subject in need thereof.
  • Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein.
  • Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder (e.g., psychiatric or neurological) as described herein.
  • Some embodiments include a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA or protein levels in a cell (e.g., hepatocyte or neuron), fluid (e.g., blood, serum, plasma, or cerebrospinal fluid (CSF)), tissue (e.g., brain or liver tissue), or organ (e.g., the brain or liver).
  • the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG mRNA levels in a cell or tissue.
  • the cell is a liver cell (e.g., hepatocyte).
  • the cell is a neuron.
  • the tissue is liver tissue.
  • the tissue is neural tissue.
  • the neural tissue is CNS tissue.
  • the neural tissue is brain tissue (e.g., neuronal, glia, or endothelial tissue).
  • the fluid is CSF.
  • the FGG mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by about 10% or more, as compared to prior to administration.
  • the FGG mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to Attorney Docket No.54462-754.601 prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by no more than about 10%, as compared to prior to administration.
  • the FGG mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases FGG protein levels in a cell, fluid (e.g., CSF) or tissue.
  • the cell is a hepatocyte.
  • the cell is a neural cell (e.g., CNS cell (e.g., brain cell)).
  • the cell is a neuronal cell.
  • the cell is a glial cell.
  • the cell is an endothelial cell.
  • the tissue is liver tissue.
  • the tissue is neural (e.g., CNS (e.g., brain)) tissue.
  • the fluid is CSF.
  • the FGG protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration.
  • the FGG protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the FGG protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount diminishes a mental disorder or disease phenotype, such as a psychiatric disorder or neurological disorder phenotype.
  • a disorder may include a disease.
  • the psychiatric disease or disorder may include depressive disorder (e.g., major depressive disorder, persistent depressive disorder, treatment resistant depression, or signs and symptoms of depression), post-traumatic stress disorder, mood disorders, anxiety disorders, eating disorders, substance-use disorders, bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders.
  • the neurological disease or disorder may include such as Alzheimer’s disease, dementia, delirium, cognitive decline, vascular Attorney Docket No.54462-754.601 dementia, headache, migraine, chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis (ME)), chronic traumatic encephalopathy, traumatic brain injury, or motor neuron disease (e.g., amyotrophic lateral sclerosis).
  • fibrinogen may be lowered enough to have a therapeutic effect on mental disorders but without significantly affecting coagulation parameters such as PT or aPTT.
  • the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves (e.g. decreases) a psychiatric disease phenotype.
  • the psychiatric disease phenotype may include a Montgomery-Asberg Depression Rating Scale (MADRS) score.
  • the psychiatric disease phenotype may include a Hamilton Depression Rating Scale score.
  • the psychiatric disease phenotype may include a sign or symptom of anxiety.
  • the psychiatric disease phenotype may include a sign or symptom of an eating disorder.
  • the psychiatric disease phenotype may include a sign or symptom of a substance-use disorder.
  • the psychiatric disease phenotype may include a sign or symptom of post-traumatic stress disorder.
  • the psychiatric disease phenotype may include a sign or symptom of bipolar disorder.
  • the psychiatric disease phenotype may include a sign or symptom of schizophrenia.
  • the psychiatric disease phenotype may include a sign or symptom of psychosis.
  • the psychiatric disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration.
  • the psychiatric disease phenotype is improved by about 10% or more, as compared to prior to administration.
  • the psychiatric disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by no more than about 10%, as compared to prior to administration.
  • the psychiatric disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the psychiatric disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition comprises an oligonucleotide that targets FGG and when administered to a subject in an effective amount improves (e.g. decreases) a neurological disease phenotype.
  • the neurological disease phenotype may include cognitive dysfunction.
  • the neurological disease phenotype may include central nervous system (CNS) amyloid plaques.
  • the neurological disease phenotype may include CNS tau accumulation.
  • the neurological disease phenotype may include cerebrospinal fluid (CSF) or plasma beta-amyloid 42, beta-amyloid 40, or the ratio of beta-amyloid 42 to beta-amyloid 40.
  • the neurological disease phenotype may include CSF or plasma tau.
  • the neurological disease phenotype may include CSF or plasma phospho-tau (such as p-tau217).
  • the neurological disease Attorney Docket No.54462-754.601 phenotype may include CSF or plasma neurofilament light chain (NfL).
  • the neurological disease phenotype may include CSF or plasma glial fibrillary acidic protein (GFAP).
  • the neurological disease phenotype may include Lewy bodies.
  • the neurological disease phenotype may include CSF alpha- synuclein.
  • the neurological disease phenotype may include headache symptoms or signs.
  • the neurological disease phenotype may include migraine symptoms or signs.
  • the neurological disease phenotype may include chronic pain symptoms or signs.
  • the neurological disease phenotype may include fibromyalgia symptoms or signs.
  • the neurological disease phenotype may include chronic fatigue syndrome (e.g., myalgic encephalomyelitis) symptoms or signs.
  • the neurological disease phenotype may include motor neuron disease (e.g., amyotrophic lateral sclerosis) symptoms or signs.
  • the neurological disease phenotype is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by about 10% or more, as compared to prior to administration.
  • the neurological disease phenotype is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by no more than about 10%, as compared to prior to administration.
  • the neurological disease phenotype is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the neurological disease phenotype is improved by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0032]
  • the composition may treat a clotting or coagulation disorder.
  • the composition may treat thrombophilia.
  • the composition may affect clotting or a clotting time.
  • the composition comprises an oligonucleotide that decreases Fibrinogen or fibrin.
  • a FGG siRNA composition may be useful as an anticoagulant, such as for treatment or prophylaxis of a coagulation or clotting disorders (e.g., venous thromboembolism, atrial fibrillation), given that significant FGG knockdown may lead to a prolonged clotting time (e.g., PT, INR or aPTT).
  • a clotting time e.g., PT, INR or aPTT
  • it is useful to lower Fibrinogen or fibrin significantly enough to prolong clotting times to clinically meaningful levels for these indications.
  • FGG knockdown may result in decreased circulating fibrinogen or fibrin.
  • Decreased circulating fibrinogen or fibrin may result in increased PT, INR and aPTT.
  • the compounds may be useful for reducing clotting.
  • Some aspects relate to a composition comprising an oligonucleotide that targets FGG and when administered to a subject in an effective amount decreases fibrinogen or fibrin.
  • Attorney Docket No.54462-754.601 [0033]
  • the prothrombin time (PT), International Normalized Ration (INR) and activated partial thromboplastin time (aPTT) levels are unchanged as compared to administration.
  • PT, INR or aPTT increases by no more than about 10%, as compared to prior to administration. In some embodiments, PT, INR or aPTT increase by no more than about 20%, no more than about 40%, no more than about 80%, no more than about 160%, no more than about 200%, no more than about 300%, no more than about 400%, or no more than about 600%, as compared to prior to administration. In some embodiments, the PT, INR or aPTT increases by 5%, 10%, 20%, 40%, 80%, 100%, 200%,400% or 600%, or by a range defined by any of the two aforementioned percentages. [0034] The composition may be used to reduce levels of fibrinogen or fibrin.
  • the fibrinogen or fibrin is reduced while leading to minimal or non-significant changes in other coagulation measurements. In some instances, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline without significant change in other coagulation measurements. In some instances, the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline.
  • the fibrinogen or fibrin is reduced by 5- 95% 5-90%, 5-80%, 5-70%, 5-50%, 5-40%, 5-30%, 10-90%, 10-80%, 10-70%, 10-50%, 10-30%, 20- 95%, 20-50%, 40-90%, 50-95%, 60-95%, or 70-90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by no more than 50%, 40%, 30%, 20%, 15%, 10%, 7% 5%, 4% 3%, 2% or no more than 1% relative to baseline.
  • the fibrinogen or fibrin is reduced by 5-95% 5-90%, 5-80%, 5-70%, 5-50%, 5-40%, 5-30%, 10-90%, 10-80%, 10-70%, 10-50%, 10-30%, 20-95%, 20-50%, 40-90%, 50-95%, 60-95%, or 70-90% relative to baseline and one or more non- fibrinogen or fibrin coagulation measurements change by 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-15%, 1-10%, 1-%, 1-5%, 1-3%, or 1-2% relative to baseline.
  • the fibrinogen or fibrin is reduced by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, or at least 90% relative to baseline and one or more non-fibrinogen or fibrin coagulation measurements change by 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-15%, 1-10%, 1-%, 1-5%, 1-3%, or 1-2% relative to baseline.
  • coagulation measurements comprises von Willebrand Factor (VWF) antigen, VWF activity, factor VIII (FVIII), alpha- 2 antiplasmin (A2AP), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), D-dimer (DD), fibrinogen, fibrin, prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), or bleeding time assay.
  • VWF von Willebrand Factor
  • VIII von Willebrand Factor
  • A2AP alpha- 2 antiplasmin
  • PAI-1 plasminogen activator inhibitor-1
  • TAT thrombin-antithrombin complex
  • DD D-dimer
  • PT prothrombin time
  • ITR international normalized ratio
  • PTT partial thromboplastin time
  • aPTT activated partial thromboplastin time
  • bleeding time assay e.g.
  • the composition comprises an oligonucleotide that targets FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.
  • siRNA small interfering RNA
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense Attorney Docket No.54462-754.601 strand, wherein the sense strand is 12-30 nucleosides in length.
  • the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the sense strand may be 14-30 nucleosides in length.
  • the composition comprises an antisense strand is 12-30 nucleosides in length.
  • the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the antisense strand may be 14- 30 nucleosides in length.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621.
  • thymine (T) may be replaced with Uracil (U).
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex.
  • the first base pair of the double-stranded RNA duplex is an AU base pair.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. [0040] In some embodiments, the antisense strand further comprises a 3’ overhang. In some embodiments, the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3’ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides.
  • Attorney Docket No.54462-754.601 [0041]
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human FGG mRNA.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human FGG mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate FGG mRNA.
  • the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate FGG mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human FGG mRNA and less than or equal to 20 human off- targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human FGG mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human FGG mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 40 human off- targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand.
  • the siRNA binds with a human FGG mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 20 human off- targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand.
  • the siRNA binds with a human FGG mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human FGG mRNA and less than or equal to 50 human off- targets, with no more than 3 mismatches in the antisense strand.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human FGG mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos.2-18).
  • siRNA minor allele frequency
  • the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense Attorney Docket No.54462-754.601 strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1742.
  • thymine (T) may be replaced with uracil (U).
  • U uracil
  • Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an A, T, C, U, or G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an A.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to a T or U.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1- Attorney Docket No.54462-754.601 1742 is modified to an G.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 1-1742 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 1- 1742 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1-1742 is modified to an C.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1743-3484.
  • thymine (T) may be replaced with uracil (U).
  • Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID Attorney Docket No.54462-754.601 NOs: 1743-3484 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an A.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to a T or U.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743- 3484 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 1743-3484 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 1743-3484 is modified to an C.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5’ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5’ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the Attorney Docket No.54462-754.601 composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3713-3748.
  • thymine (T) may be replaced with uracil (U).
  • Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an A.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an A.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to a T or U.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713-3748 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3713-3748 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3713- 3748 is modified to an C.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3713- 3748 is modified to an C.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: Attorney Docket No.54462-754.601 3749-3784 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3749-3784.
  • thymine (T) may be replaced with uracil (U).
  • Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an A.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to a T or U.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749- 3784 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 1 and position 14, Attorney Docket No.54462-754.601 position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3749-3784 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3749-3784 is modified to an C.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the sense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3879-3941 or 4020-4021.
  • thymine (T) may be replaced with Uracil (U).
  • Any of the aforementioned siRNAs may include an antisense strand where the 5’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U or T.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879- Attorney Docket No.54462-754.601 3941 or 4020-4021 is modified to an A.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an A.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an T or U.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to a T or U.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879- 3941 or 4020-4021 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020- 4021 is modified to an C.
  • position 6 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.
  • position 1 and position 6, position 1 and position 19, position 6 and position 19, or position 1, position 6, and position 19 of any one of SEQ ID NOs: 3879-3941 or 4020-4021 is modified to an C.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand further comprises a 3’ overhang.
  • the 3’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 3’ overhang comprises 1, 2, or more nucleosides.
  • the 3’ overhang comprises 2 nucleosides.
  • the antisense strand further comprises a 5’ overhang.
  • the 5’ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers.
  • the 5’ overhang comprises 1, 2, or more nucleosides.
  • the 5’ overhang comprises 2 nucleosides.
  • the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3’ end.
  • the composition comprises an Attorney Docket No.54462-754.601 oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 3942-4002 or 4022-4023.
  • thymine (T) may be replaced with Uracil (U).
  • Any of the aforementioned siRNAs may include a sense strand wherein the 3’ nucleoside has been modified to an A.
  • any one of the aforementioned siRNAs may include a sense strand sequence wherein the 5’ nucleoside has been modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A, T, C, U, or G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • position 14 (from the 5’ end) of the sense strand of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an A.
  • position 1 (from the 5’ end of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to a T or U.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942- 4002 or 4022-4023 is modified to an G.
  • position 1 and position 14, position 1 and position 19, position 14 and position 19, or position 1, position 14, and position 19 of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an G.
  • position 1 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • position 14 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • position 19 (from the 5’ end) of any one of SEQ ID NOs: 3942-4002 or 4022-4023 is modified to an C.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in any of Tables 3-7.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Tables 3-7. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA.
  • NHS non-human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.
  • a sense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an A.
  • a sense strand sequence of an siRNA in any one of Tables 3-6 is modified by substitution of the nucleoside to an A at position 19 (from the 5’ end).
  • an antisense strand sequence of an siRNA in any one of Tables 3-7 is modified by substitution of the 3’ nucleoside to an U. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 66B.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 66B. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • NHS non- human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 79.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Attorney Docket No.54462-754.601 Table 79, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • NEP non-human primate
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in any of Table 83.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Table 83, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Table 83, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any Table 83. In some embodiments, the siRNA is cross- reactive with a non-human primate (NHP) FGG mRNA.
  • NHS non-human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 87.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • NEP non-human primate
  • any of the aforementioned siRNAs may include a sense strand Attorney Docket No.54462-754.601 where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 93.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA.
  • NHS non-human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 97.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 97. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • NEP non-human primate
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 101.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 101.
  • the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 105.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 105. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 109.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 109. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • NHS non- human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one Attorney Docket No.54462-754.601 of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 113.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 113. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 117.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 117. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • NHS non- human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 121.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 121, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Attorney Docket No.54462-754.601 Table 121, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 121.
  • the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 125.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 125. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • NHS non- human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 166.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 166. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one Attorney Docket No.54462-754.601 of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 170.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 170. In some embodiments, the siRNA is cross-reactive with a non- human primate (NHP) FGG mRNA.
  • NHS non- human primate
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0068] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 Attorney Docket No.54462-754.601 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0069] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end).
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0072] In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense Attorney Docket No.54462-754.601 strand sequence of an siRNA of subset G, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset G.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A.
  • any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end). Any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U. [0073]
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset H, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset H.
  • the siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A. Any of the aforementioned siRNAs may include a sense strand where the 3’ nucleoside has been modified to an A at position 19 (from the 5’ end).
  • any one of the aforementioned siRNAs may include an antisense strand sequence wherein the 5’ nucleoside has been modified to a U.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 352, 1003, 1011, 1278, or 3785.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 352. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 352. The sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a Attorney Docket No.54462-754.601 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1003.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1003.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1011.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 1011.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 1278.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 1278.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3785.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3785.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 2094, 2745, 2753, or 3020.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 2094, 2745, 2753, or 3020.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2094.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2094.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2745.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2745.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 2753.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 2753.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand Attorney Docket No.54462-754.601 may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3020.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3020.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3723, 3724, 3726, or 3747.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3723, 3724, 3726, or 3747.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3723. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3723. The sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3724.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3724.
  • the sense strand may include any Attorney Docket No.54462-754.601 internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3726. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3726. The sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3747.
  • the sense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the sense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with an antisense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end).
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3759, 3760, 3762, 3783, or 3790.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the antisense strand may include a GalNAc moiety connected at one of the ends (e.g., 5’ end or 3’ end).
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3759.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the Attorney Docket No.54462-754.601 antisense strand comprises the nucleoside sequence of SEQ ID NO: 3759.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3760.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3760.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3762.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3762.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3783.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3783.
  • the antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3790. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3790. The antisense strand may include any internucleoside linkages or nucleoside modifications described herein.
  • the antisense strand Attorney Docket No.54462-754.601 may include an overhang (e.g., 2 bases on a 5’ or 3’ end when paired with a sense strand).
  • the sense strand may include a GalNAc moiety connected at one of the ends.
  • the siRNA comprises a sense strand having a sequence in accordance with any sequence of Table 1A.
  • the siRNA comprises a sense strand sequence as shown in Table 1A. Table 1A.
  • the sense strand sequence comprises or consists of sequence at least 75% identical to any one of Table 1A, at least 80% identical to any one of Table 1A, at least 85% identical to of any one of Table 1A, at least 90% identical to any one of Table 1A, or at least 95% identical to any one of Table 1A.
  • the sense strand sequence comprises or consists of the sequence of any one of Table 1A, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand sequence comprises or consists of the sequence of any one of Table 1A, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to Table 1A.
  • the sense strand may comprise a modification pattern described herein.
  • the sense strand may comprise a lipid moiety.
  • the sense strand may comprise a GalNAc moiety.
  • the siRNA comprises an antisense sense strand sequence as shown in Table 1B. Table 1B.
  • the siRNA comprises an antisense strand having a sequence in accordance with any of Table 1B.
  • the antisense strand sequence comprises or consists of sequence at least 75% identical to any one of Table 1B, at least 80% identical to any one of Table 1B, at least 85% identical to of any one of Table 1B, at least 90% identical to any one of Table 1B, or at least 95% identical to any one of Table 1B.
  • the antisense strand sequence comprises or consists of the sequence of any one of Table 1B, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand sequence comprises or consists of the sequence of any one of Table 1B, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to Table 1B. The antisense strand may comprise a modification pattern described herein.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 3.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 3.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 3, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense Attorney Docket No.54462-754.601 strand comprises a sequence of a sense or antisense strand in Table 3, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 3.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 4.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 4.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 4, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 4.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 5.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 5.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 5, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 5.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 6.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 6.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 6, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense Attorney Docket No.54462-754.601 sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 6.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 7.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 7.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 7, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 7, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 7.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 8.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 8.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 8, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 8, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 8.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 9B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 9B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand Attorney Docket No.54462-754.601 sequence in Table 9B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 9C.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 9C.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9C, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 9C, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 9C.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 18B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 18B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 18B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 18B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 22B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 22B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 22B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 22B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 22B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • Attorney Docket No.54462-754.601 [00110]
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 26B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 26B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 26B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 26B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 26B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 31B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 31B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 31B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 31B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 31B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 33B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 33B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 33B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 33B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 33B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 37B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 37B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 37B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 37B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 37B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 42B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 42B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 42B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 42B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 42B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 42B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 42B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 47B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or Attorney Docket No.54462-754.601 antisense strand sequence in Table 47B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 47B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 47B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 47B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 67B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 67B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 67B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 67B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 67B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 79B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 79B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 79B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 79B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 79B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 85.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 85.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 85, or a sequence thereof having 3 or 4 Attorney Docket No.54462-754.601 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 85, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 85.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 89.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 89.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 89, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 89, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 89.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 93.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 93.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 93, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 93, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 93.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 97.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 97.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 97, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 97, or a sequence thereof having 1 or Attorney Docket No.54462-754.601 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 97.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 101.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 101.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 101, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 101, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 101.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 105.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 105.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 105, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 105, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 105.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 109.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 109.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 109, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 109, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand Attorney Docket No.54462-754.601 sequence in Table 109.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 113.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 113.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 113, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 113, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 113.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 117.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 117.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 117, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 117, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 117.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 121.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 121.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 121, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 121, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 121.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 125.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 125.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 125, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 125, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in 125185.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 142.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 142.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 142, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 142, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 142.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 183.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 183.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 183, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 183, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 183.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 187.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 187.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 187, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 187, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 187.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the siRNA comprises a sense strand or antisense strand having a sequence in accordance with the sense strand or antisense strand sequence of an siRNA in Table 190B.
  • the sense strand or antisense strand comprises a sequence at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense strand or antisense strand sequence in Table 190B.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 190B, or a sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense strand comprises a sequence of a sense or antisense strand in Table 190B, or a sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand or antisense sequence comprises or consists of a sequence 100% identical to a sense strand or antisense strand sequence in Table 190B.
  • the sense strand or antisense strand may comprise any modifications described herein.
  • the sense strand or antisense strand may comprise a lipid moiety or a GalNAc moiety.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO is 12-30 nucleosides in length.
  • the ASO is 14-30 nucleosides in length.
  • the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers.
  • the ASO is 15-25 nucleosides in length.
  • the ASO is 20 nucleosides in length.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human FGG mRNA sequence such as SEQ ID NO: 3621; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 3621.
  • Modification patterns [00135]
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier.
  • the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages.
  • a phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur.
  • Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include decreased toxicity or improved pharmacokinetics.
  • the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs.
  • the duplex comprises blunt-ends at the 5’or 3’ ends of each strand.
  • One strand (antisense strand) is complementary to a target mRNA.
  • Each end of the antisense strand has one to five phosphorothioate bonds.
  • the 5’ end has an optional phosphate mimic such as a vinyl phosphonate.
  • the oligonucleotide is used to knock down a target mRNA or a target protein.
  • the sense strand has the same sequence as the target mRNA.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers.
  • the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages.
  • the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises the modified nucleoside.
  • the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2'-O-methoxyethyl, 2'-O-alkyl, 2'-O-allyl, 2'-fluoro, or 2'-deoxy, or a combination thereof.
  • the modified nucleoside comprises a LNA.
  • the modified nucleoside comprises a 2’,4’ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HNA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2'-O-methoxyethyl group. In some embodiments, the modified nucleoside comprises a 2'-O-alkyl group. In some embodiments, the modified nucleoside comprises 2’-O-methoxyethyl. In some embodiments, the modified nucleoside comprises a methoxyethyl.
  • position 4 of the sense strand may comprise a methoxyethyl nucleoside such as a 2’-O- methoxyethyl thymine.
  • the modified nucleoside comprises 2'-O-methyl.
  • the modified nucleoside comprises a 2'-O-allyl group.
  • the modified nucleoside comprises a 2'-fluoro group.
  • the modified nucleoside comprises a 2'- deoxy group.
  • the modified nucleoside comprises a 2'-O-methyl nucleoside, 2'- deoxyfluoro nucleoside, 2'-O-N-methylacetamido (2'-O-NMA) nucleoside, a 2'-O- dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside, or 2'- ara-F, or a combination thereof.
  • the modified nucleoside comprises a 2'-O-methyl nucleoside.
  • the modified nucleoside comprises a 2'-deoxyfluoro nucleoside.
  • the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleoside comprises one or more 2’- fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2’-O-alkyl modified nucleoside.
  • the modified nucleoside comprises a 2’-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an acyclic nucleic acid. In some embodiments, the acyclic nucleic is a glycol nucleic acid. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics. [00139] In some embodiments, the modified nucleoside comprises a glycol nucleic acid (GNA).
  • GAA glycol nucleic acid
  • a GNA may comprise the following structure: Attorney Docket No.54462-754.601 [00140] [00141] In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure: wherein the base can be any pyrimidine or purine. [00142] In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site: are independently an H or a 3’ or 5’ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.
  • the oligonucleotide comprises a phosphate mimic.
  • the phosphate mimic comprises methylphosphonate.
  • An example of a nucleotide that comprises a methylphosphonate is shown below: methylphosphonate 2’-O-Methyl Uridine).
  • Attorney Docket No.54462-754.601 [00144]
  • the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs.
  • the duplex comprises blunt-ends at the 5’or 3’ ends of each strand.
  • One strand (antisense strand) is complementary to a target mRNA.
  • Each end of the antisense strand has one to five phosphorothioate bonds.
  • the 5’ end has an optional phosphate mimic such as a vinyl phosphonate.
  • the oligonucleotide is used to knock down a target mRNA or a target protein.
  • the sense strand has the same sequence as the target mRNA.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers.
  • the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleoside
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof.
  • the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5’ end of the sense strand.
  • the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3’ end of the sense strand.
  • the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5’ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3’ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5’ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3’ end of the ASO.
  • the sense strand comprises at least three modified nucleosides, wherein the three modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprises a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside, a 2’-O-methyl modified nucleoside, and 2’-O-methoxyethyl.
  • the antisense strand is combination of 2’-fluoro and 2’-O-Methyl modifications.
  • each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the sense strand comprises at least a 2’-fluoro modified nucleoside and a 2’-O-methyl modified nucleoside.
  • the oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I), or modified versions thereof.
  • the oligonucleotide may include pyrimidines.
  • pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.
  • the sense strand comprises purines and pyrimidines.
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-O-methyl and 2’-O-methoxyethyl.
  • all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methoxyethyl.
  • all purine nucleosides comprise 2’-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’ -O-methyl and 2’-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O- methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methoxyethyl.
  • all pyrimidine nucleosides comprise 2’-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl.
  • the sense strand may include a 2’ deoxy nucleoside.
  • at least one nucleotide at position 4 or 5 of the sense strand comprises a 2’-O-methoxyethyl modified nucleoside.
  • at least one nucleotide of the sense strand from position 6 to 9 comprise a 2’-fluoro-modified nucleoside.
  • At least two nucleotides of the sense strand at position 6 to 9 comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2’-fluoro- modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2’-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2’-O-methyl modified nucleoside.
  • At least two nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2’-O-methyl modified nucleoside.
  • any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are Attorney Docket No.54462-754.601 modified with a mixture of 2’-fluoro and 2’-O-methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro; all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and all purine nucleo
  • all purine nucleosides comprise 2’-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2’-fluoro and 2’-O- methyl; all purine nucleosides comprise 2’-O-methyl, and all pyrimidine nucleosides comprise 2’-fluoro.
  • all pyrimidine nucleosides comprise 2’-fluoro, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl; all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides are modified with a mixture of 2’-fluoro and 2’-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2’-O-methyl, and all purine nucleosides comprise 2’- fluoro. [00153] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety.
  • the hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the hydrophobic moiety may include a lipid such as a fatty acid.
  • the hydrophobic moiety may include a hydrocarbon.
  • the hydrocarbon may be linear.
  • the hydrocarbon may be non-linear.
  • the hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or ⁇ -tocopherol, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety.
  • the sugar moiety may include an N- acetyl galactose moiety (e.g., a N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety.
  • the sugar moiety may include 1, 2, 3, or more sugar molecules.
  • the sugar moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the sugar moiety may include an N-acetyl galactose moiety.
  • the sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety.
  • the sugar moiety may include an N- acetyl glucose moiety.
  • the sugar moiety may include N-acetylglucosamine (GlcNAc) moiety.
  • the sugar moiety may include a fucose moiety.
  • the sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages since they may target or bind a mannose receptor such as CD206.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc N-acetylgalactosamine
  • GalNAc Attorney Docket No.54462-754.601 may be useful for hepatocyte targeting. Since FGG may be secreted by the liver, the decreased FGG quantity in the liver resulting from the liver targeted FGG siRNA may result in a decrease in fibrinogen or FGG protein in circulation, and a related decrease in the central nervous system (CNS) (e.g., brain), or cerebrospinal fluid (CSF).
  • the GalNAc moiety may include 1, 2, 3, or more GalNAc molecules.
  • the GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • Non-limiting examples of GalNAc ligands are shown in FIG.1 and FIG.2.
  • the oligonucleotide is conjugated to the GalNAc ligand in FIG.1.
  • J indicates a point of attachment to an oligonucleotide.
  • J is at a 5’ end of the oligonucleotide.
  • J is at a 3’ end of the oligonucleotide.
  • n may be any number.
  • n may be 1-10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a range defined by any two of the aforementioned integers. In some embodiments, n is 2. In embodiments in which n is 2 and the oligonucleotide is connected at J, the GalNAc moiety may be referred to as “GalNAc#1” or “GalNAc1.” [00158] In some embodiments, the oligonucleotide is conjugated to the GalNAc ligand in FIG.2. The wavy line in FIG.1 indicates a point of attachment to an oligonucleotide.
  • the wavy line is at a 5’ end of the oligonucleotide. In some embodiments, the wavy line is at a 3’ end of the oligonucleotide. In embodiments in which the oligonucleotide is connected at the wavy line, the GalNAc moiety may be referred to as “GalNAc#23” or “GalNAc23.”
  • the oligonucleotide may include purines. Examples of purines include adenine (A), guanine (G), or inosine (I), or modified versions thereof.
  • the oligonucleotide may include pyrimidines.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines.
  • all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • 2’-O-methyl may include 2’-O-methyl. Where 2’-O-methyl modifications are described, it is contemplated that a 2’-methyl modification may be included, and vice versa.
  • pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines.
  • pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified Attorney Docket No.54462-754.601 pyrimidines.
  • purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the oligonucleotide comprise 2’-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2’-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2’- O-methyl modified purines.
  • pyrimidines of the oligonucleotide comprise 2’-O- methyl modified pyrimidines, and purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all purines of the oligonucleotide comprise 2’-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2’-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2’-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2’-fluoro modified purines.
  • the oligonucleotide comprises a particular modification pattern.
  • position 9 counting from the 5’ end of the of a strand of the oligonucleotide may have a 2’F modification.
  • position 9 of a strand of the oligonucleotide is a pyrimidine
  • all purines in a strand of the oligonucleotide have a 2’OMe modification.
  • position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide.
  • both of these pyrimidines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • position 9 and only two other bases between positions Attorney Docket No.54462-754.601 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2’F modifications in a row, then any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.
  • position 9 of a strand of the oligonucleotide when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2’F modification in a strand of the oligonucleotide.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that a strand of the oligonucleotide does not have three 2’F modifications in a row.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.
  • position 9 of a strand of the oligonucleotide can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of a strand of the oligonucleotide.
  • a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine.
  • all purines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row.
  • the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide.
  • position nine of the sense strand comprises a 2’-fluoro-modified pyrimidine; all purines of the sense strand comprises 2’-O- methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2’-fluoro- Attorney Docket No.54462-754.601 modified pyrimidine, provided there are not three 2’-fluoro-modified pyrimidines in a row; the odd- numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even- numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises a 2’-fluoro-modified purine.
  • all pyrimidines of the sense strand comprise 2’-O-methyl modified purines.
  • 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purine, provided there are not three 2’-fluoro-modified purine in a row.
  • the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotide.
  • position nine of the sense strand comprises a 2’-fluoro- modified purine; all pyrimidine of the sense strand comprises 2’-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2’-fluoro-modified purines, provided there are not three 2’-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’- fluoro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- modifed nucleotides.
  • all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O- methyl modified purines or 2’-fluoro-modified purines.
  • the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2’-O-methyl modified purines or 2’-fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide.
  • positions 5, 7, and 8 of the sense strand comprise 2’-fluoro- Attorney Docket No.54462-754.601 modifed nucleotides.
  • all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro-modified pyrimidines.
  • the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides.
  • the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides, 2’-O-methyl modified nucleotides and unmodified deoxyribonucleotides.
  • position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2’-fluoro-modifed nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2’-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2’-O-methyl modified pyrimidines or 2’-fluoro- modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2’-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2’-fluoro-modified nucleotides and unmodified deoxyribonucleotide.
  • the moiety includes a negatively charged group attached at a 5’ end of the oligonucleotide. This may be referred to as a 5’-end group.
  • the negatively charged group is attached at a 5’ end of an antisense strand of an siRNA disclosed herein.
  • the 5’-end group may be or include a 5’-end phosphorothioate, 5’-end phosphorodithioate, 5’-end vinylphosphonate (5’-VP), 5’- end methylphosphonate, 5’-end cyclopropyl phosphonate, or a 5’-deoxy-5’-C-malonyl.
  • the 5’-end group may comprise 5’-VP.
  • the 5’-VP comprises a trans-vinylphosphonate or cis- vinylphosphonate.
  • the 5’-end group may include an extra 5’ phosphate.
  • a combination of 5’-end groups may be used.
  • the oligonucleotide includes a negatively charged group.
  • the negatively charged group may aid in cell or tissue penetration.
  • the negatively charged group may be attached at a 5’ or 3’ end (e.g., a 5’ end) of the oligonucleotide. This may be referred to as an end group.
  • the end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl.
  • the end group may include an extra 5’ phosphate such as an extra 5’ phosphate.
  • a combination of end groups may be used.
  • the oligonucleotide includes a phosphate mimic.
  • the phosphate mimic comprises vinyl phosphonate.
  • the vinyl phosphonate comprises a trans-vinylphosphonate.
  • the vinyl phosphonate comprises a cis- vinylphosphonate.
  • the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.
  • the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5’ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3’ end.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic moiety.
  • the hydrophobic moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the hydrophobic moiety may include a lipid such as a fatty acid.
  • the hydrophobic moiety may include a hydrocarbon.
  • the hydrocarbon may be linear.
  • the hydrocarbon may be non-linear.
  • the hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or ⁇ -tocopherol, or a combination thereof.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a hydrophobic ligand or moiety.
  • the hydrophobic ligand or moiety comprises cholesterol.
  • the hydrophobic ligand or moiety comprises a cholesterol derivative.
  • the hydrophobic ligand or moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety Attorney Docket No.54462-754.601 s attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises a hydrophobic ligand or moiety attached at a 3’ or 5’ terminus of the oligonucleotide.
  • a hydrophobic moiety is attached to the oligonucleotide (e.g., a sense strand and/or an antisense strand of a siRNA).
  • a hydrophobic moiety is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl. The hydrophobic moiety may include an esterified lipid. [00180] In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a lipid attached at a 3’ or 5’ terminus of the oligonucleotide.
  • a lipid is attached at a 3’ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or ⁇ -tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, litrocholyl, docosanyl, docosahexaenyl, or myristyl.
  • the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12. The lipid moiety may be esterified. [00181] In some embodiments, the oligonucleotide comprises any aspect of the following structure: .
  • the oligonucleotide comprises any aspect of the following structure: some embodiments, the oligonucleotide comprises any aspect of the following structure: Attorney Docket No.54462-754.601 some embodiments, the oligonucleotide comprises any aspect of the following structure: aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown.
  • n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group.
  • the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 4-18 carbons.
  • the lipid moiety comprises an alcohol or ether. [00182] In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 2.
  • the example lipid moieties in Table 2 are shown attached at a 5’ end of an oligonucleotide, in which the 5’ terminal phosphate of the oligonucleotide is shown with the lipid moiety.
  • a lipid moiety in Table 2 may be attached at a different point of attachment than shown.
  • the point of attachment of any of the lipid moieties in the table may be at a 3’ oligonucleotide end.
  • the lipid is used for targeting the oligonucleotide to a non- hepatic cell or tissue.
  • the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some Attorney Docket No.54462-754.601 embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons. [00184]
  • the hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered.
  • a carbocycle examples include phenyl or cyclohexyl.
  • the linker may include a phenyl.
  • the linker may include a cyclohexyl.
  • the lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g., 5’ or 3’ phosphate) of the oligonucleotide.
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g., the para, meta, or ortho phenyl configuration).
  • the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4 substitution pattern (e.g., the para phenyl configuration).
  • the lipid may be attached to the carbocycle in the 1,4 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,3 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the 1,2 substitution pattern relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide.
  • the lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.
  • the lipid moiety may comprise or consist of the following structure the lipid moiety comprises the following structure: embodiments, the lipid moiety comprises or consist of the following structure: .
  • the dotted line indicates a covalent connection.
  • the covalent connection may between an end of the sense or antisense strand. For example, Attorney Docket No.54462-754.601 the connection may be to the 5’ end of the sense strand.
  • n is 0-3. In some embodiments, n is 1-3.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.
  • the lipid moiety may be attached at a 5’ end of the oligonucleotide.
  • the 5’ end may have one phosphate linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have two phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have three phosphates linking the lipid moiety to a 5’ carbon of a sugar of the oligonucleotide.
  • the 5’ end may have one phosphate connected to the 5’ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety.
  • the 5’ end may have two phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety.
  • the 5’ end may have three phosphates connected to the 5’ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety.
  • the sugar may include a ribose.
  • the sugar may include a deoxyribose.
  • the sugar may be modified a such as a 2’ modified sugar (e.g., a 2’-O-methyl or 2’-fluoro ribose).
  • a phosphate of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • Two phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • Three phosphates of the 5’ end may include a modification such as a sulfur in place of an oxygen.
  • the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.
  • Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate.
  • a strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate.
  • Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows: , Attorney Docket No.54462-754.601 . some embodiments, n is 1-3.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons.
  • any one of the phosphoramidite reagents may be reacted to a 5’ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety.
  • the phosphoramidite reagents is reacted to a 5’ end of a sense strand of an siRNA.
  • the sense strand may then be hybridized to an antisense strand to form a duplex.
  • the hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature.
  • the temperature may be gradually reduced.
  • the temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands.
  • the temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands.
  • the temperature may be below a melting temperature of the sense and antisense strands.
  • the lipid may be attached to the oligonucleotide by a linker.
  • the linker may include a polyethyleneglycol (e.g., tetraethyleneglycol).
  • the modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition.
  • the modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue. 2.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a sugar moiety.
  • the sugar moiety may include an N- acetyl galactose moiety (e.g., an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g., an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety.
  • the sugar moiety may include 1, 2, 3, or more sugar molecules.
  • the sugar moiety may be attached at a 3’ or 5’ Attorney Docket No.54462-754.601 terminus of the oligonucleotide.
  • the sugar moiety may include an N-acetyl galactose moiety.
  • the sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety.
  • the sugar moiety may include an N- acetyl glucose moiety.
  • the sugar moiety may include N-acetylglucosamine (GlcNAc) moiety.
  • the sugar moiety may include a fucose moiety.
  • the sugar moiety may include a mannose moiety.
  • N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206.
  • the sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte.
  • the GalNAc moiety may bind to an asialoglycoprotein receptor.
  • the GalNAc moiety may target a hepatocyte.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety.
  • GalNAc may be useful for hepatocyte targeting.
  • the GalNAc moiety may include a bivalent or trivalent branched linker.
  • the oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker.
  • the GalNAc moiety may include 1, 2, 3, or more GalNAc molecules.
  • the GalNAc moiety may be attached at a 3’ or 5’ terminus of the oligonucleotide.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting.
  • GalNAc N-acetylgalactosamine
  • the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3’ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5’ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g., attached to a 5’ end of the sense strand, or attached to a 3’ end of the sense strand).
  • the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g., attached to a 5’ end of the antisense strand, or attached to a 3’ end of the antisense strand).
  • the composition comprises a GalNAc ligand attached at a 3’ or 5’ terminus of the oligonucleotide.
  • compositions comprising an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises a GalNAc moiety.
  • the GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below.
  • oligonucleotide represented by Formula (I) or (II): or a salt thereof, wherein Attorney Docket No.54462-754.601 J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR 6 , or if z is 1, Y is C(R 6 )2; Q is selected from: C3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R
  • each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2.
  • z is 3 and Y is C.
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -C(O)N(R 7 )2, -N(R 7 )C(O)R 7 , - N(R 7 )C(O)N(R 7 )2, -OC(O)N(R 7 )2, -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , and -S(O)R 7 .
  • Q is selected from C5-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2.
  • Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, and -NH2.
  • Q is selected from phenyl.
  • Q is selected from cyclohexyl.
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, - OP(O)(OR 7 )S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O-)S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2- NR 7 .
  • R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O-)O-, -SP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, -OP(O)(O- )S-, and -OP(OR 7 )O-.
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, - OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and -OP(OR 7 )O-. In some embodiments, R 1 is selected from - OP(O)(OR 7 )O- and -OP(OR 7 )O-.
  • R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , and -S(O)R 7 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from -OR 7 , -OC(O)R 7 , -SR 7 , and -N(R 7 ) 2 .
  • R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from -OR 7 and - Attorney Docket No.54462-754.601 OC(O)R 7 .
  • R 3 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 .
  • R 3 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 ) 2 .
  • R 3 is selected from -OR 7 - and -OC(O)R 7 .
  • R 4 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 )2, -C(O)R 7 , -OC(O)R 7 , and -S(O)R 7 .
  • R 4 is selected from -OR 7 -SR 7 , -OC(O)R 7 , and -N(R 7 )2.
  • R 4 is selected from -OR 7 - and -OC(O)R 7 .
  • R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 )2, -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 )2, and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 .
  • each R 7 is independently selected from C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, and -SH.
  • Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, and C1-3 alkyl;
  • R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O-)O-, -OP(S)(O-)O-, -OP(O)(S-)O-, and - OP(OR 7 )O-;
  • R 2 is C1 alkyl substituted with -OH or -OC(O)CH3; Attorney Docket No.54462-754.601
  • the oligonucleotide (J) is attached at a 5’ end or a 3’ end of the oligonucleotide.
  • the oligonucleotide comprises DNA.
  • the oligonucleotide comprises RNA.
  • the oligonucleotide comprises one or more modified internucleoside linkages.
  • the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof.
  • the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages.
  • the compound binds to an asialoglycoprotein receptor.
  • the compound targets a hepatocyte.
  • J is the oligonucleotide: Attorney Docket No.54462-754.601 include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide.
  • J may include one or more additional phosphates linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • Attorney Docket No.54462-754.601 [00199] Some embodiments include the following, where J is the oligonucleotide: include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • J is the oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is Attorney Docket No.54462-754.601 an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide: [00202] Some embodiments include the following, where the phosphate or “5’” indicates a connection to the oligonucleotide: [00203] Some embodiments include the following, where J is the oligonucleotide: Attorney Docket No.54462-754.601 include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • Some embodiments include the following, where J is the oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety.
  • J may include one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J may include one or more phosphates linking to the oligonucleotide.
  • J may include a Attorney Docket No.54462-754.601 phosphate linking to the oligonucleotide.
  • J may include one or more phosphorothioates linking to the oligonucleotide.
  • J may include a phosphorothioate linking to the oligonucleotide.
  • compositions comprising an oligonucleotide that inhibits the expression of a target gene, wherein the oligonucleotide comprises a GalNAc moiety.
  • the GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below.
  • oligonucleotide represented by Formula (III), (IV), or (V): Formula IV, or Attorney Docket No.54462-754.601 Formula V, or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 0 to 20; v is independently selected from any value from 0 to 20; each n is selected from any value from 0 to 20; each m is selected from any value from 0 to 20; each p is selected from any value from 0 to 1; each w is selected from any value from 0 to 20; t is selected from any value from 0 to 1; x is selected from any value from 0 to 1; r is selected from any value from 0 to 20; u is selected from any value from 0 to 20; Q is selected from: C3-20 cyclic, heterocyclic or acyclic linker optionally substituted with one or more substituents independently selected from hal
  • J is an oligonucleotide
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “L96,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: Attorney Docket No.54462-754.601 .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “NAG37,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GluGalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or Attorney Docket No.54462-754.601 more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J and K are independently H, a GalNAc moiety or oligonucleotides: [00213]
  • the structures in these compounds in some instances are attached to the oligonucleotide (J or K) and referred to as “ademA GalNAc, ademG GalNAc, ademC GalNAc, or ademU GalNAc” depending on the base used in the nucleotide.
  • 2-4 GalNAc moieties are attached oligonucleotide.
  • J and K may in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J and K in some instances Attorney Docket No.54462-754.601 comprises one or more phosphates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphate linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • R is an oligonucleotide: Attorney Docket No.54462-754.601 Attorney Docket No.54462-754.601 or Attorney Docket No.54462-754.601 .
  • the structure in this compound attached to the oligonucleotide (R) in some instances is referred to as H1, H2, H3, H4, H5, H6, H7, or H9, and are examples of GalNAc moieties.
  • R in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • R in some instances comprises one or more phosphates linking to the oligonucleotide.
  • R in some instances comprises a phosphate linking to the oligonucleotide.
  • R in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • R in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J is an oligonucleotide: .
  • J The structure in this compound attached to the oligonucleotide (J) may be referred to as “K2GalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide and X is S or O: .
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “ST23,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide:
  • J The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “GalNAc23,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J or K comprises an oligonucleotide:
  • the structures in these compounds in some instances are attached to the oligonucleotide (J or K), referred to as “PyrGalNAc”, “PipGalNAc” and “TEG-GalNAc” are examples of GalNAc moieties.
  • 2-4 GalNAc moieties are attached oligonucleotide.
  • J and K in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphate linking to the oligonucleotide.
  • J and K in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J and K in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • Nu is an oligonucleotide:
  • L-9 is an example of a GalNAc moiety.
  • Nu in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • Nu in some instances comprises one or more phosphates linking to the oligonucleotide.
  • Nu in some instances comprises a phosphate linking to Attorney Docket No.54462-754.601 the oligonucleotide.
  • Nu in some instances comprises one or more phosphorothioates linking to the oligonucleotide. Nu in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J is an oligonucleotide:
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Sirius GalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • [00227] Provided herein are sugar moieties comprising the following structures, where J is an oligonucleotide:
  • J The structures in this compound attached to the oligonucleotide (J) in some instances are referred to as GLS-5 and GLS-15 and are examples of GalNAc moieties.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: Attorney Docket No.54462-754.601
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Olix GalNAc,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J and J’ is an oligonucleotide or a GalNAc moiety:
  • the structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “GalNAc G1b,” and is an example of a GalNAc moiety.
  • J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphate linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where B is a nucleic acid base, and J and J’ is an oligonucleotide or a GalNAc moiety: Attorney Docket No.54462-754.601 [00234]
  • the structure in this compound attached to the oligonucleotide or a GalNAc moiety (J or J’) in some instances is referred to as “1gT3,” and is an example of a GalNAc moiety.
  • J or J’ in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphate linking to the oligonucleotide.
  • J or J’ in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J or J’ in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide and X is an optional linker:
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “5gn2c6,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • X is a carbon or heteroatom linker to J. In some instances, the heteroatom in linker X is an N or O.
  • J is an oligonucleotide: Attorney Docket No.54462-754.601
  • the structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “[Gal-6]s[Gal-6]s[Gal-6],” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • sugar moieties comprising the following structure, where J is an oligonucleotide: The structure in this compound attached to the oligonucleotide (J) in some instances is referred to as “Janssen,” and is an example of a GalNAc moiety.
  • J in some instances comprises one or more phosphates Attorney Docket No.54462-754.601 or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates or phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises one or more phosphates linking to the oligonucleotide.
  • J in some instances comprises a phosphate linking to the oligonucleotide.
  • J in some instances comprises one or more phosphorothioates linking to the oligonucleotide.
  • J in some instances comprises a phosphorothioate linking to the oligonucleotide.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfnNfsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 2S: 5’-nsnsnnnNfnNfNfNfnnnnnnnnsn- 3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 3S: 5’-nsnsnnnNfnNfnNfnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 4S: 5’-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides.
  • the sense strand comprises modification pattern 5S: 5’-nsnsnnnNfnNfNfNfnnnnnnnsnsnN-moiety-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides.
  • the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a sugar moiety.
  • the sense strand comprises modification pattern 6S: 5’-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 7S: 5’-nsnsnnNfNfNfNfNfnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 8S: 5’-nsnsnnnnNfNfNfNfnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 9S: 5’-nsnsnnnnnNfNfNfnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 10S: 5'- nsnsnnNfNfnNfNfnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 11S: 5'-nsnsnnNfnnnNfnnnnnnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 12S: 5'-snnnnNfNfnNfNfnnnnNfnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 13S: 5'- snnnnNfNfnNfdNnNfNfnnNfnnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 14S: 5'-snnNfNfnnnnNfnnnnNfnNfNfnnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 15S: 5'-snnNfnNfnNfNfdNnNfNfnnNfnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 16S: 5'- snnnnNfnNfNfNfNfnnnnnnnnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 17S: 5'-snnnnnNfNfNfNfnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 18S: 5'-snnnnNfNfnNfNfnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 19S: 5'-snnnnNfnnnNfnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 20S: 5'-snnnnnNfNfNfNfnNfnnnnnnnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 21S: 5'- snnnnnnNfNfNfNfnnnnnnnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 22S: 5'-snnnnNfNfnNfNfnNfnnnnnnnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 23S: 5'-snnnnNfnNfNfdTnnnnnnnnsnsn-3', wherein “dT” is deoxythymidine, “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 24S: 5'- snnnnNfNfnnNfNfnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 25S: 5'-snnnnnNfNfnNfnnnnnnnnnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 26S: 5'-snnnnnnNfnNfNfnnnnnnnnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 27S: 5'-snnnnnnnNfNfnNfnnnnnnnnsn- 3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 28S: 5'-snnnnnnnnNfnNfnnnnnnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 29S: 5'-snnnnnnnNfNfNfnnnnnnnsn- 3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 30S: 5'- snnnnmnNfNfNfNfnnnmnnnnnnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 31S: 5'-snnnnmnNfNfNfNfnnnmnnnnnnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified Attorney Docket No.54462-754.601 nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 32S: 5'-snnnnmnNfNfNfntmnnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 33S: 5'-snnnnnmNfNfNfNfnnnmnnnnnnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 34S: 5'-snnnnmnNfNfNfNfnnnnnmnnnnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 35S: 5'-snnnnmnNfNfNfNfnnnnmnnnnnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 36S: 5'-snnnnmnNfNfNfNfnnnntmnnnnnnsnsn-3’, wherein “nm” is a 2’-O-methoxyethyl-modified nucleoside, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 37S: 5'-snnnnmNfnNfNfNfNfnnnmnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 38S: 5'-snnnnmnNfNfNfNfnnmnnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 39S: 5'-snnnnNfnNfNfNfdnnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 40S: 5'- snnnnnNfnnNfnNfnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 41S: 5'-snnnnNfnnNfNfNfNfnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 42S: 5'-snnnnNfNfNfNfNfnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 43S: 5'-snnnnNfnnNfNfnNfnnnnnnnsn- 3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 44S: 5'-snnnnmNfnNfNfNfnntmnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, Attorney Docket No.54462-754.601 and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 45S: 5'-snnnnmnNfNfNfNfnnntmnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 46S: 5'-snnnnmnNfNfNfNfnntmnnnnnnnsnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl- modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 47S: 5'-snnnnNfNfnnNfnnnnnnnsn-3’, wherein “Nf” is a 2’- fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 48S: 5'- snnnnnnNfNfNfNfnnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 49S: 5'-snnnnNfnNfnNfnnnnnnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 50S: 5'-snnnnnnNfNfNfnnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 51S: 5'- snnnmnNfNfNfNfnnnmnnnnnnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, “nm” is a 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 52S: 5'-snnnnNfnNfNfNfdNnnnnnnnnsnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 53S: 5'- snnnnNfnNfNfdTnnnnnnnnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 54S: 5'-snnnnNfnNfnNfNfnnnnnnnnsn-3’, “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 55S: 5'- snnnnNfnnNfNfnnnnnnnnnsn-3’, “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 56S: 5'-snnnnNfnnnNfNfnnnnnnnnsn-3’, “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5’-nsNfsnNfnNfnNfnNfnnnNfnNfnsnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a Attorney Docket No.54462-754.601 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 2AS: 5’-nsNfsnnnNfnNfNfnnnnNfnNfnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 3AS: 5’-nsNfsnnnNfnnnnnnnnNfnNfnnnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 4AS: 5’-nsNfsnNfnNfnnnnnnnNfnNfnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 5AS: 5’-nsNfsnnnnnnnnnnnnNfnNfnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 6AS: 5’-nsNfsnnnNfnnNfnnnnNfnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 7AS: 5’-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 8AS: 5’-nsNfsnnnnnnnnnnnnnnnsnsn-3’ , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 9AS: 5’-nNfnNfnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 10AS: 5'- nsNfsnNfnnnNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 11AS: 5'-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 12AS: 5'-nsNfsndTndNnNfnNfndNnNfndNnNfnsnsn-3' , wherein “Nf” is a 2’- fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 13AS: 5'-nsNfsndTndNnNfnNfndNndTndNndTnsnsn-3' , wherein “Nf” is a 2’- fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 14AS: 5'-nsNfsnnnNfnnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 15AS: 5'- Attorney Docket No.54462-754.601 dTsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “dT” is deoxythymidine, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 16As: 5'- NfsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3', wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 17AS: 5'- nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 18AS: 5'-nsNfsnNfnNfnnnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 19AS: 5'-nsNfsnNfnnNfNfnNfnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 20AS: 5'- nsNfsnNfnnNfnnnnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 21AS: 5'-nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3' , wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 22AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 23AS: 5'- nsNfsnnnNfnNfnNfnNfnNfnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’- O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 24AS: 5'-nsNfsnnnNfnNfnNfnNfnNfnnnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 25AS: 5'-nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 26AS: 5'- nsNfsnnNfnNfNfnnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 27AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 28AS: 5'-nsNfsnnnNfNfnnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 29AS: 5'- Attorney Docket No.54462-754.601 nsNfsnnnNfNfnnnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 30AS: 5'-nsNfsnnNfnNfNfnNfnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 31AS: 5'-nsNfsnnNfnNfnnNfnnnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the sense strand comprises modification pattern 32AS: 5'- nsNfsnnNfnNfNfnNfnnnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’ O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 33AS: 5’-nsNfsnnnnNfnnnnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 34AS: 5’-nsNfsnnNfnNfnNfnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 35AS: 5’- nsNfsnNfnnNfnnnnNfnNfnNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 36AS: 5’-nsNfsnNfnnNfnnnnNfnNfnsNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 37AS: 5’-nsNfsnNfnnNfnnnnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 38AS: 5’- nsNfsnNfnnNfnnnnNfnNfsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 39AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnNfnNfsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 40AS: 5’-nsNfsnNfnnNfnnNfnNfnNfnNfnsnsn-3’, wherein “Nf” is a 2’-fluoro- modified nucleoside, “n” is a 2’-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the antisense strand comprises modification pattern 41AS: 5’- nsNfsnNfnnnfnnNfnnNfnNfsnsn-3’, wherein “Nf” is a 2’-fluoro-modified nucleoside, “n” is a 2’-O- methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, Attorney Docket No.54462-754.601 18AS, 19AS, 20AS, or 21AS.
  • the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.
  • the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS .
  • the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS .
  • the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, Attorney Docket No.54462-754.601 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, Attorney Docket No.54462-754.601 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, Attorney Docket No.54462-754.601 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 52S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand Attorney Docket No.54462-754.601 comprises pattern 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 55S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 1AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 2AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 3AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 4AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 5AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 6AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 7AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, Attorney Docket No.54462-754.601 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 8AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 9AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 10AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 11AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 12AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 13AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 14AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 15AS..
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 16AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 17AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, Attorney Docket No.54462-754.601 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 18AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 19AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 20AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 21AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 22AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 23AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 24AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 25AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 26AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 27AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, Attorney Docket No.54462-754.601 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 28AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 29AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 30AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 31AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 32AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 33AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 34AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 35AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 36AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 37AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises Attorney Docket No.54462-754.601 pattern 38AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 39AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 40AS.
  • the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S and the antisense strand comprises pattern 41AS.
  • the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 33AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, 40AS, or 41AS.
  • the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, or 56S.
  • the sense strand or the antisense strand comprises modification pattern ASO1. [00244] In some embodiments, the sense strand or the antisense strand comprises a modification pattern of Table C. In some embodiments, the sense strand or the antisense strand comprises a modification pattern of Table D. In some embodiments, the sense strand or the antisense strand comprises a modification pattern of Table E. [00245] In some embodiments, the sense strand comprises a modification pattern sequence of Table C. Table C. Attorney Docket No.54462-754.601 [00246] In some embodiments, the antisense strand comprises a modification pattern of Table D. Table D.
  • the sense strand comprises a modification pattern sequence of Table C. In some embodiments, the antisense strand comprises a modification pattern sequence of Table D. [00248] In some embodiments, a sense strand sequence may omit a 3’ AUU of a sense strand sequence of Table E. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-18 of a sense strand of Table E. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-19 of a sense strand of Table E. In some embodiments, the sense strand comprises the nucleoside sequence of positions 1-20 of a sense strand of Table E.
  • the sense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table E omitting an AUU sequence.
  • the sense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table E and omits at least one nucleoside comprising an A, a U, a UU, or an AUU.
  • an antisense strand sequence of Table E may omit a 5’ U and 3’ UU of an antisense strand sequence.
  • the antisense strand comprises the nucleoside sequence of positions 1-18 of an antisense strand in Table E.
  • the antisense strand comprises the nucleoside sequence of positions 2-19 of an antisense strand in Table E. In some embodiments, the antisense strand comprises the nucleoside sequence of positions 2-21 of an antisense strand of Table E. In some embodiments, the antisense strand comprises a sequence that is at least 90% identical to a nucleoside sequence in Table E omitting a 5’ U and a 3’ UU.
  • the antisense strand can be a nucleoside sequence that is at least 90% identical to a nucleoside sequence in Table E and omits at least one nucleoside comprising a U or UU [00249]
  • the siRNA modification strand comprises a modification pattern shown in Table E. Table E. Attorney Docket No.54462-754.601 [00250]
  • purines of the sense strand comprise 2’-fluoro modified purines.
  • purines of the sense strand comprise 2’-O-methyl modified purines.
  • purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • all purines of the sense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. [00251] In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified pyrimidines. [00252] In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-fluoro modified purines, and pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2’-O-methyl modified purines, and pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and purines of the sense strand comprise 2’-O-methyl modified purines.
  • pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines
  • purines of the sense strand comprise 2’-fluoro modified purines.
  • all purines of the sense strand comprise 2’-fluoro modified purines
  • all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all purines of the sense strand comprise 2’-O-methyl modified purines
  • all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all purines of the sense strand comprise 2’-fluoro modified purines, and all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines.
  • all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2’- fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-fluoro modified pyrimidines, and all purines of the sense strand comprise 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2’-fluoro modified purines. [00254] In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines.
  • purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. [00255] In some embodiments, pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2’-fluoro modified purines, and pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines.
  • purines of the antisense strand comprise 2’-O-methyl modified purines
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines.
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines
  • purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines
  • purines of the antisense strand comprise Attorney Docket No.54462-754.601 a mixture of 2’-fluoro and 2’-O-methyl modified purines.
  • pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and purines of the antisense strand comprise 2’- O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2’-O- methyl modified pyrimidines, and purines of the antisense strand comprise 2’-fluoro modified purines. [00257] In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines.
  • all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2’-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines.
  • all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2’-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2’-O-methyl modified purines.
  • all pyrimidines of the antisense strand comprise 2’-O-methyl modified pyrimidines
  • all purines of the antisense strand comprise 2’-fluoro modified purines.
  • the modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency.
  • the siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject.
  • the modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.
  • the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs.
  • the duplex comprises single-stranded 2 nucleotide overhangs are at the 3’ ends of each strand.
  • One strand (antisense strand) is complementary to a FGG mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5’ end has an optional phosphate mimic such as a vinyl phosphonate.
  • the oligonucleotide is used to knock down a FGG mRNA or a target protein.
  • the sense strand has the same sequence as the FGG mRNA.
  • the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern.
  • position 9 counting from the 5’ Attorney Docket No.54462-754.601 end of the sense strand may have a 2’F modification.
  • position 9 of the sense strand is a pyrimidine
  • all purines in the sense strand have a 2’OMe modification.
  • position 9 is the only pyrimidine between positions 5 and 11 of the sense stand
  • position 9 is the only position with a 2’F modification in the sense strand.
  • position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2’F modification in the sense strand.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of pyrimidines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2’OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2’F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2’F modification in the sense strand.
  • any combination of 2’F modifications can be made that give three 2’F modifications in total.
  • all combinations of purines having the 2’F modification are allowed that have three to five 2’F modifications in total, provided that the sense strand does not have three 2’F modifications in a row.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.
  • position 9 of the sense strand can be a 2’deoxy. In these cases, 2’F and 2’OMe modifications may occur at the other positions of the sense strand.
  • the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules. [00263] In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.
  • compositions comprising an oligonucleotide that targets FGG and when administered to a cell decreases expression of FGG, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one Attorney Docket No.54462-754.601 internucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence
  • the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand.
  • any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified purines and all pyr
  • any one of the following is true with regard to the antisense strand: all purines comprise 2’-fluoro modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise a mixture of 2’-fluoro and Attorney Docket No.54462-754.601 2’-O-methyl modified pyrimidines; all purines comprise 2’-O-methyl modified purines, and all pyrimidines comprise 2’-fluoro modified pyrimidines; all pyrimidines comprise 2’-fluoro modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines comprise 2’-O-methyl modified pyrimidines, and all purines comprise a mixture of 2’-fluoro and 2’-O-methyl modified purines; all pyrimidines
  • the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5’ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3’ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O- methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O-methoxyethyl modified pyrimidines; or (i
  • any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2’-O-methyl and 2’-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O- methoxyethyl modified pyrimidines; (b) all purines comprise 2'-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2’-fluoro and 2’-O- methoxyethyl modified pyrimidines; or (ii) a mixture of 2’-fluoro, 2’-O-methyl, and 2’-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2'-O-methoxyethyl modified pur
  • a deoxy nucleoside may be included in the sense strand.
  • the sense strand includes the deoxy nucleoside.
  • the deoxy nucleoside may be at nucleoside position 9 of the sense strand.
  • the sense strand does not include a deoxy nucleoside.
  • the deoxy nucleoside of the sense strand may be otherwise unmodified.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, Attorney Docket No.54462-754.601 or 186.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, or 186 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, or 186 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, or 186.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, or 186.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in any of Tables 8-15, 18A, 22A, 26A, 31A, 33A, 37A, 42A, 47A, 67A, 79A, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 141, 182, or 186.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 8A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 8A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 8A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 8B.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 8B.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 8B.
  • the siRNA may include any different Attorney Docket No.54462-754.601 internucleoside linkage modifications or nucleoside modifications different from those in Table 8B.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 18A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 18A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table18Aor a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 18A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table18A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 18A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 22A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 22A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 22A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 22A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 26A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 26A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 26A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 26A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 31A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 31A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 31A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 31A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 33A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 33A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 33A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 37A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 37A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 37A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 37A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, Attorney Docket No.54462-754.601 or at least 95% identical, to a sense and/or antisense strand sequence in Table 42A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 42A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 42A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 42A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 47A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 47A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 47A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 47A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 67A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 67A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 67A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 79A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79A or Attorney Docket No.54462-754.601 a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 79A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 79A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 79A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 84.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 84.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 84.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 88.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 88 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 88 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 88.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 88.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 88.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 92.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Attorney Docket No.54462-754.601 Table 92 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 92.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 92.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 96.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 96.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 96.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 100.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 100.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 100.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 100.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 104.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 104 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand Attorney Docket No.54462-754.601 sequence of an siRNA in Table 104.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 104.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 104.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 108.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 108.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 108.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 108.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 112.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 112.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 112.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 112.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 116.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 116.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 116.
  • the siRNA may include any different Attorney Docket No.54462-754.601 internucleoside linkage modifications or nucleoside modifications different from those in Table 116.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 120.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 120.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 120.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 120.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 124.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 124.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 124.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 124.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 141.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 141 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 141 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 141.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 141.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 141.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 182.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 182 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 182 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 182.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 182.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 182.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 186.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 186 or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 186 or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 186.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 186.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 186.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense and/or antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to a sense and/or antisense strand sequence in Table 190A.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 190A or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions.
  • the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 190A or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 190A.
  • the siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 190A.
  • the siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 190A.
  • the siRNA may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3591-3594.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3591-3594.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3591-3594.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3795-3802.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3795-3802.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3795-3802.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3813-3843.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3813-3843. The sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3813-3843.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3591.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3591, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand Attorney Docket No.54462-754.601 comprises the nucleoside sequence of SEQ ID NO: 3591.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3591.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3592.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3592.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3592. The sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3593.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3593.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3593.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3594.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3594.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3640-3676.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3640-3676, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3640-3676, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of any Attorney Docket No.54462-754.601 one of SEQ ID NOs: 3640-3676.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3640-3676.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3651.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3651. The sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3651. The sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3652.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3652.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3652.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3654.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3654. The sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3594. The sense strand may include some unmodified internucleoside linkages or nucleosides. The sense strand may include GalNAc1 or another GalNAc moiety. [00306] In some embodiments, the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3675.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises the nucleoside sequence of SEQ ID NO: 3675.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: Attorney Docket No.54462-754.601 3675. The sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the sense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3795.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the sense strand comprises the nucleoside sequence of SEQ ID NO: 3795.
  • the sense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3795.
  • the sense strand may include some unmodified internucleoside linkages or nucleosides.
  • the sense strand may include GalNAc1 or another GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3595-3598.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3595-3598. The antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3595-3598.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3803-3808.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3803-3808.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3803-3808.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3844-3878. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the Attorney Docket No.54462-754.601 antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3844-3878.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3844-3878.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3595. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3595.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3595.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3596.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3596.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3596.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety. [00313] In some embodiments, the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3597.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3597.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3597. The antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3598.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3598.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3598.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to any one of SEQ ID NOs: 3677-3712.
  • the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of any one of SEQ ID NOs: 3677-3712. The antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NOs: 3677-3712.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3687.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3687.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3687.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety. [00317]
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3688.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3688.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3688. The antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3747.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3747.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3747.
  • the antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the antisense strand comprises a nucleoside sequence at least 85% identical to SEQ ID NO: 3690.
  • the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690, and 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand comprises the nucleoside sequence of SEQ ID NO: 3690.
  • the antisense strand may include any different internucleoside linkage modifications or nucleoside modifications different from those in SEQ ID NO: 3690. The antisense strand may include some unmodified internucleoside linkages or nucleosides.
  • the antisense strand may include a GalNAc moiety.
  • the composition comprises an oligonucleotide that inhibits the expression of FGG, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO).
  • ASO antisense oligonucleotide
  • the ASO comprises modification pattern ASO1: 5’-nsnsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3’ (SEQ ID NO: 3640), wherein “dN” is any deoxynucleotide, “n” is a 2’-O-methyl or 2’-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate linkage.
  • the ASO comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 46S, 47S, 48S, 49S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, or 21AS.
  • the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. Attorney Docket No.54462-754.601 [00323] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome.
  • the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof.
  • Some embodiments include administering a composition described herein to a subject with the disorder.
  • the administration treats the disorder in the subject.
  • the composition treats the disorder in the subject.
  • the treatment comprises prevention, inhibition, improvement, or reversion of the disorder (e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)) in the subject.
  • the disorder e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)
  • Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder.
  • Some embodiments relate to a method of preventing, inhibiting, improving, or reversing a disorder in a subject in need thereof.
  • Some embodiments include administering a composition described herein to a subject with the disorder.
  • the administration prevents, inhibits, improves, or reverses the disorder in the subject.
  • the composition prevents, inhibits, improves, or reverses the disorder in the subject.
  • Some embodiments relate to a method of preventing a disorder (e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)) in a subject in need thereof.
  • Some embodiments relate to use of a composition described herein in the method of preventing the disorder.
  • Some embodiments include administering a composition described herein to a subject with the disorder.
  • the administration prevents the disorder in the subject.
  • the composition prevents the disorder in the subject.
  • Some embodiments relate to a method of inhibiting a disorder (e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject. Attorney Docket No.54462-754.601 [00329] Some embodiments relate to a method of reversing a disorder (e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)) in a subject in need thereof.
  • a disorder e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)
  • use of a composition described herein in the method of inhibiting the disorder include administering a composition described herein to a subject with the disorder. In some embodiments,
  • Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject. [00330] Some embodiments relate to a method of improving a disorder (e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)) in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of improving the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration improves the disorder in the subject.
  • a disorder e.g., mental disorder (e.g., psychiatric disorder or neurological disorder)
  • the administration improves the disorder in the subject.
  • the composition improves the disorder in the subject.
  • the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is subcutaneous. In some embodiments, the administration is by injection.
  • A. Disorders [00332] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof.
  • a disorder can include a disease.
  • the disorder is a mental disorder. In some embodiments, the mental disorder is a psychiatric disorder or neurological disorder.
  • the psychiatric disorder or neurological disorder may comprise a hepatic disorder, a brain disorder, a CNS disorder, a CSF disorder, or a combination thereof.
  • the disorder comprises a psychiatric disorder.
  • psychiatric disorders include depressive disorders, such as major depressive disorder, persistent depressive disorder, treatment resistant depression and signs or symptoms of depression.
  • Further non- limiting examples of psychiatric disorders include post-traumatic stress disorder, mood disorders, anxiety disorders (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, social phobia, etc.), eating disorders, substance-use disorders (e.g., alcohol use disorders, prescription medicines use disorders, illegal drug use disorders, psychoactive substance-use disorders, etc.) bipolar disorder, personality disorders, schizophrenia and schizoaffective disorders. .
  • the disorder is a depressive disorder.
  • depressive disorders include major depressive disorder, persistent depressive disorder, or treatment resistant depression.
  • the depressive disorder comprises or consists of major depressive disorder.
  • the depressive disorder comprises or consists of persistent depressive disorder.
  • the depressive disorder comprises or consists of treatment resistant depression.
  • the depressive disorder is treatment resistant depression.
  • Treatment resistant depression may include depression that does not respond (e.g., within an acceptable period of time) to first, second, or third line treatments.
  • the disorder includes a sign or symptom of depression.
  • Exemplary signs or symptoms of depression may include a persistent feeling of sadness or loss of interest, Attorney Docket No.54462-754.601 apathy, feelings of hopelessness and sadness, anxiety, agitation, and restlessness.
  • Exemplary signs or symptoms of depression may be any sign or symptom of depression within the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is hereby incorporated by reference.
  • the disorder comprises post-traumatic stress disorder (PTSD).
  • Exemplary signs or symptoms of PTSD include recurrent, unwanted distressing memories of the traumatic event, flashbacks, upsetting dreams or nightmares about the traumatic event, negative thoughts about yourself, other people or the world, memory problems, difficulty experiencing positive emotions, or feeling emotionally numb.
  • Exemplary signs or symptoms of PTSD may be any sign or symptom of PTSD within the DSM-5.
  • the disorder comprises mood disorders.
  • An exemplary mood disorder includes dysthymia.
  • the disorder comprises anxiety disorders.
  • Exemplary anxiety disorders include generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, social phobias, and social anxiety disorder.
  • GAD generalized anxiety disorder
  • OCD obsessive-compulsive disorder
  • panic disorder e.g., panic disorder, social phobias, and social anxiety disorder.
  • Signs or symptoms of anxiety disorders include a feeling of restlessness, being easily fatigued, having difficulty concentration, and being irritable.
  • Exemplary signs or symptoms of anxiety disorders e.g., GAD, OCT, etc.
  • the disorder comprises eating disorders.
  • Exemplary eating disorders include anorexia nervosa, bulimia nervosa, and binge-eating disorder.
  • Exemplary signs and symptoms of eating disorders include extremely restricted eating, emaciation, intense fear of gaining weight, brittle nails and hair, eating unusually large amounts of food in a specific amount of time, such as a 2-hour period, eating even when you're full or not hungry, and eating until you're uncomfortably full.
  • Exemplary signs or symptoms of eating disorders may be any sign or symptom of eating disorders within the DSM-5.
  • the disorder comprises substance-use disorders.
  • Exemplary substance-use disorders include alcohol-use disorder, prescription drug use disorder, illegal drug use disorder, solvent abuse, and “legal high” abuse.
  • Exemplary signs and symptoms of substance-use disorders include intense urges for the substance that block out other thoughts, needing more of the substance to get the same effect over time, and failure in attempts to stop using the substance.
  • Exemplary signs or symptoms of substance- use disorders may be any sign or symptom of substance-use disorders within the DSM-5.
  • the disorder comprises bipolar disorder.
  • the bipolar disorder comprises bipolar I disorder.
  • the bipolar disorder comprises bipolar II disorder.
  • the bipolar disorder comprises cyclothymic bipolar disorder.
  • the bipolar disorder comprises mixed feature bipolar disorder.
  • Exemplary signs and symptoms of bipolar disorder include experiencing a manic episode and experiencing a major depressive episode.
  • Exemplary signs or symptoms of bipolar disorder may be any sign or symptom of bipolar disorder within the DSM-5.
  • the disorder comprises a personality disorder.
  • Exemplary personality disorders include borderline personality disorder, antisocial personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, and schizoid personality disorder.
  • Exemplary signs and symptoms of personality disorders include impulsive and risky behavior, unstable or fragile self-image, up and down moods, and suicidal behavior or threats of self-injury.
  • Exemplary signs or symptoms of personality disorder may be any sign or symptom of personality disorder within the DSM-5.
  • the disorder comprises schizophrenia.
  • Exemplary schizophrenia signs and symptoms include delusions, hallucinations, disorganized thinking, and loss of interest or motivation in life.
  • the signs and symptoms comprise positive symptoms (e.g., hallucinations or delusions).
  • the signs and symptoms comprise negative symptoms (e.g., lack of interest or emotionally flat).
  • Exemplary signs or symptoms of schizophrenia may be any sign or symptom of schizophrenia within the DSM-5.
  • the disorder comprises schizoaffective disorders.
  • Exemplary schizoaffective disorders include the bipolar type schizoaffective disorder and depressive type schizoaffective disorder.
  • Exemplary signs and symptoms of schizoaffective disorders include delusions, hallucinations, impaired communication, and playful or unusual behavior.
  • the disorder comprises a neurological disorder.
  • neurological disorders include Alzheimer’s disease, dementia, cognitive decline, vascular dementia.
  • Further non-limiting examples of neurological disorders include headache, migraine (e.g., with aura and/or without aura), chronic pain, fibromyalgia, chronic fatigue syndrome (e.g., myalgic encephalomyelitis), motor neuron disease (e.g., Amyotrophic Lateral Sclerosis (ALS)), Parkinson’s disease.
  • the disorder comprises dementia.
  • dementia comprises vascular dementia.
  • dementia comprises Lewy body dementia. In some embodiments, dementia comprises frontotemporal dementia. In some embodiments, dementia comprises Alzheimer’s disease. In some embodiments, dementia comprises mixed dementia. Exemplary signs and symptoms of dementia include memory loss, difficulty communicating, difficulty with visual and spatial abilities, difficulty reasoning or problem-solving, difficulty with coordination and motor functions, and confusion and disorientation. [00345] In some embodiments, Alzheimer’s disease comprises early-onset Alzheimer’s disease. Early- onset Alzheimer’s disease may occur in subjects under the age of 65 years old. In some embodiments, Alzheimer’s disease comprises late-onset Alzheimer’s disease. In some embodiments, Alzheimer’s disease comprises common Alzheimer’s disease. In some embodiments, Alzheimer’s disease comprises genetic Alzheimer’s disease.
  • the disorder comprises delirium.
  • Exemplary forms of delirium include hyperactive delirium, hypoactive delirium, and mixed delirium.
  • Exemplary signs and symptoms of delirium include agitation, disorientation, delusional thoughts, hallucinations, poor memory, difficulty speaking and trouble understanding speech.
  • Attorney Docket No.54462-754.601 In some embodiments, the disorder comprises cognitive decline.
  • Exemplary forms of cognitive decline include mild cognitive impairment, dementia, primary progressive aphasia, corticobasal degeneration, primary progressive aphasia, and progressive supranuclear palsy.
  • Exemplary signs and symptoms of cognitive decline include forgetfulness, feelings of being overwhelmed, difficulty understanding directions or instructions, inability to organize tasks, and an increased impulsiveness.
  • the disorder comprises a headache.
  • the headache comprises a migraine (e.g., with aura or without aura). Headaches may include sinus headaches, tension headache, migraine, and cluster headache.
  • Exemplary signs and symptoms of headaches include pain (e.g., deep and constant) in the cheekbones, forehead, bridge of the nose, the cranium, or the back of the neck, aura, photophobia, phonophobia, and emesis.
  • the disorder comprises chronic pain.
  • chronic pain comprises fibromyalgia.
  • Exemplary signs and symptoms of fibromyalgia include muscular pain, fatigues, depression, anxiety, sleeplessness, headache, and difficulty concentrating.
  • Exemplary chronic pain disorders include postsurgical pain, post-trauma pain, low back pain, cancer pain, arthritis pain, muscular pain, and neuropathic pain (e.g., diabetic neuropathy).
  • the disorder comprises chronic fatigue syndrome (also referred to as myalgic encephalomyelitis).
  • chronic fatigue syndrome also referred to as myalgic encephalomyelitis.
  • Exemplary signs and symptoms of chronic fatigue syndrome include extreme fatigue that lasts for extended periods of time (e.g., for at least six months) that cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., joint or muscular), malaise, forgetfulness, anxiety, and depression.
  • the disorder comprises chronic traumatic encephalopathy.
  • Exemplary signs and symptoms of chronic traumatic encephalopathy include cognitive impairment, dementia, agitation, disorientation, playful or unusual behavior, depression, suicidal behavior or threats of self- injury, and movement disorders.
  • the disorder comprises traumatic brain injury.
  • traumatic brain injury Exemplary signs and symptoms of traumatic brain injury include cognitive deficits, motor deficits, sensory or perceptual deficits, communication or language deficits, functional deficits, social difficulties, regulatory disturbances, personality changes and mood disorders, and traumatic epilepsy.
  • the disorder comprises a motor neuron disease.
  • the motor neuron disease is amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Exemplary forms of motor neuron diseases include progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), ALS, and primary lateral sclerosis (PLS).
  • Exemplary signs and symptoms of motor neuron diseases include motor control difficulties (e.g., difficulty walking or completing normal daily activities), muscular weakness, slurred speech, difficulty swallowing, muscle cramps and twitching (e.g., in the arms, shoulders, or tongue), and inappropriate crying, laughing or yawning, [00354]
  • the disorder comprises a coagulation or clotting disorder.
  • the coagulation or clotting disorder comprises Hemophilia, Von Willebrand disease or clotting factor deficiencies.
  • the coagulation or clotting disorder comprises a Attorney Docket No.54462-754.601 thrombophilia.
  • the thrombophilia comprises an inherited thrombophilia. In some embodiments, the thrombophilia comprises an acquired thrombophilia. In some embodiments, the coagulation or clotting disorder comprises a hypercoagulable state. In some embodiments, the hypercoagulable state comprises cancer. In some embodiments, the hypercoagulable state comprises atrial fibrillation. In some embodiments, the hypercoagulable states comprises a post-surgical period or immobility. In some embodiments, the coagulation or clotting disorder comprises arterial thrombosis or thromboembolism. In some embodiments, the coagulation or clotting disorder comprises venous thrombosis or thromboembolism.
  • the venous thromboembolism comprises deep venous thrombosis. In some embodiments, the venous thromboembolism comprises pulmonary embolism. In some embodiments, the venous thromboembolism comprises thrombophlebitis. In some embodiments, disclosed herein is a method of treating a subject having a clotting or coagulation disorder or a thrombophilia, comprising administering an effective amount of a composition described herein. In some embodiments, the method comprises increasing the prothrombin time, International Normalized Ratio, or the activated partial thromboplastin time compared to a baseline.
  • the disorder may be diagnosed with the use of a questionnaire or a scoring system. In some cases, the disorder is diagnosed according to DSM-5 criteria. In some cases, the disorder is diagnosed by a healthcare professional (e.g., physician or the like). [00356] In some embodiments, the disorder comprises one or more disorders (e.g., any of the disorders disclosed herein). In some embodiments, the disorder comprises two disorders. In some embodiments, the disorder comprises three disorders. In some embodiments, the disorder comprises four disorders. In some embodiments, the disorder comprises five disorders. B. Subjects [00357] Some embodiments of the methods described herein include treatment of a subject.
  • Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans.
  • the subject is a vertebrate.
  • the subject is an animal.
  • the subject is a mammal.
  • the subject is a dog.
  • the subject is a cat.
  • the subject is a cattle.
  • the subject is a mouse.
  • the subject is a rat.
  • the subject is a primate.
  • the subject is a monkey.
  • the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human. [00358] In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is 45 years old or greater. In some embodiments, the subject is 50 years old or greater. In some embodiments, the subject is 55 years old or greater. In some embodiments, the subject is 60 years old or greater. In some embodiments, the subject is 65 years old or greater.
  • the subject is 70 years old or greater. In some embodiments, the subject is 75 years old or greater. In some embodiments, the subject is 80 years old or greater. In some embodiments, the subject is 85 years old or greater.
  • Attorney Docket No.54462-754.601 [00359] In some embodiments, the subject has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more, or a range defined by any two of the aforementioned integers. In some embodiments, the subject is overweight. In some embodiments, the subject has a BMI of 25 or more.
  • the subject has a BMI of 25-29. In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30 or more. In some embodiments, the subject has a BMI of 30-39. In some embodiments, the subject has a BMI of 40-50. In some embodiments, the subject has a BMI of 25-50. [00360] In some embodiments, the subject has a personal history with the disorder. In some embodiments, the subject has a familial history with the disorder. In some embodiments, the subject is at high risk of contracting the disorder. [00361] In some embodiments, the subject has a coagulation or clotting disorder.
  • the coagulation or clotting disorder comprises Hemophilia, Von Willebrand disease or clotting factor deficiencies.
  • the subject has a thrombophilia.
  • the thrombophilia comprises an inherited thrombophilia.
  • the thrombophilia comprises an acquired thrombophilia.
  • the subject has a hypercoagulable state.
  • the hypercoagulable state comprises cancer.
  • the hypercoagulable state comprises atrial fibrillation.
  • the hypercoagulable states comprises a post- surgical period or immobility.
  • the subject has arterial thrombosis or thromboembolism.
  • the subject has venous thrombosis or thromboembolism.
  • the venous thromboembolism comprises deep venous thrombosis.
  • the venous thromboembolism comprises pulmonary embolism.
  • the venous thromboembolism comprises thrombophlebitis.
  • C. Genotyping [00362] Some embodiments of the methods described herein include treatment of a subject. [00363] Disclosed herein, in some embodiments, are systems, methods and kits for detecting one or more genotypes. In some embodiments, the genotypes described herein are detected using suitable genotyping devices (e.g., array, sequencing).
  • a sample is obtained from the subject or patient indirectly or directly.
  • the sample may be obtained by the subject.
  • the sample may be obtained by a healthcare professional, such as a nurse or physician.
  • the sample may be derived from virtually any biological fluid or tissue containing genetic information, such as blood.
  • Methods disclosed herein for detecting a genotype in a sample from a subject comprise analyzing the genetic material in the sample to detect at least one of a presence, an absence, and a quantity of a nucleic acid sequence encompassing the genotype of interest.
  • the genotype is a genotype at risk for developing Alzheimer’s disease or dementia.
  • the subject is a heterozygous carrier of APOE4.
  • the subject is a homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous carrier of FGG rs148685782-G (A108) or FGG rs6063-C (G191). In some embodiments, the subject is a homozygous carrier of FGG rs148685782-G (A108) or FGG rs6063-C (G191). Attorney Docket No.54462-754.601 [00365] In some embodiments, a polygenic risk score is calculated. In some embodiments, the polygenic risk score includes APOE. In some embodiments, the polygenic risk score does not include APOE.
  • the polygenic risk score includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 variants. In some embodiments, the polygenic risk score includes at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000 or more variants. In some embodiments, the polygenic risk score includes at least 1000, 10,000, 100,000, 1,000,000 or more variants.
  • the steps of calculating a polygenic risk score comprise providing a sample from a subject, optionally purifying DNA from the sample by processing the sample, assaying the optionally processed sample to detect genotypes of at least two genetic loci in the sample, processing the genotypes to produce a polygenic risk score (PRS), calculating the percentile risk of the subject by comparing the PRS to a reference population and selecting a therapy to treat a disease or disorder of the subject based on the percentile.
  • PRS polygenic risk score
  • a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk scope in the upper 50 th percentile, 40 th percentile, 30 th percentile, 20 th percentile, 10 th percentile, 5 th percentile, 4 th percentile, 3 rd percentile, 2 nd percentile, or 1 st percentile.
  • a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk score in the upper 20 th percentile.
  • a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk score in the upper 40 th percentile.
  • Nucleic acid-based detection techniques that may be useful for the methods herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, and next generation sequencing.
  • qPCR quantitative polymerase chain reaction
  • FISH fluorescent in situ hybridization
  • the methods involve TaqManTM qPCR, which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acids with a hydrolysable probe specific to a target nucleic acid.
  • the methods involve hybridization and/or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, and probe arrays.
  • Non-limiting amplification reactions include, but are not limited to, qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any other nucleic acid amplification known in the art.
  • qPCR includes use of TaqManTM methods.
  • An additional exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence of a genotype provided herein.
  • a non-limiting method is one employed in Anal Chem.2013 Feb 5; 85(3):1932-9.
  • detecting the presence or absence of a genotype comprises sequencing genetic material from the subject.
  • Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony Attorney Docket No.54462-754.601 sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis.
  • SMRT single-molecule real-time
  • Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.
  • the methods provided herein for determining the presence, absence, and/or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR.
  • genetic material is obtained from a sample of a subject, e.g., a sample of blood or serum.
  • nucleic acids are extracted using any technique that does not interfere with subsequent analysis.
  • this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol.
  • this technique uses phenol, chloroform, or any combination thereof.
  • this technique uses cesium chloride.
  • this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA.
  • this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich.
  • the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis.
  • the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.
  • D. Baseline measurements Some embodiments of the methods described herein include obtaining a baseline measurement from a subject.
  • the baseline measurement is a mental disorder (e.g., psychiatric or neurological disorder) baseline measurement.
  • a baseline measurement is obtained from the subject prior to treating the subject.
  • baseline measurements include a baseline measurement of Montgomery-Asberg Depression Rating Scale (MADRS); a baseline Hamilton Depression Rating Scale-17 (e.g., scale ranges from 0 to 52 with a higher score indicating worsening symptoms of depression); baseline anxiety symptoms and/or signs, baseline eating disorder symptoms and/or signs, baseline substance-use disorder symptoms and/or signs, baseline post-traumatic stress disorder symptoms and/or signs, baseline bipolar disorder symptoms and/or signs, baseline schizophrenia symptoms and/or signs, and baseline psychosis symptoms and/or signs.
  • the baseline measurement includes an aspect of any of Tables 1A-1C and 2A-2B.
  • the baseline measurement may include a baseline fibrinogen measurement, a baseline fibrin measurement, a baseline FGG mRNA measurement, or a baseline FGG protein measurement.
  • the baseline measurement may include a baseline clotting measurement, a baseline prothrombin time (PT) measurement, a baseline International Normalized Ratio (INR) measurement, or a baseline activated partial thromboplastin time (aPTT) measurement.
  • PT prothrombin time
  • INR International Normalized Ratio
  • aPTT baseline activated partial thromboplastin time
  • the baseline measurement is obtained by the subject filling out a questionnaire. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. [00374] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g. HPLC) assay.
  • an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g. HPLC) assay.
  • the baseline measurement is obtained by PCR.
  • the baseline measurement is a baseline Montgomery-Asberg Depression Rating Scale (MADRS) score.
  • the MADRS scale may range from 0 to 60 with a higher score indicating worsening symptoms of depression.
  • the MADRS generally includes a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. It was designed as an adjunct to the HDRS to be, in some cases, more sensitive to changes brought on by antidepressants or other forms of treatment. A higher MADRS score indicates more severe depression than a lower score.
  • the overall score ranges from 0 to 60.
  • the baseline MADRS score comprises a numerical value such as a number of points.
  • the numerical value is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 5556, 57, 58, 59, or 60, or a range defined by any two of the aforementioned numerical values.
  • the numerical value is 1-5. In some embodiments, the numerical value is 6-10. In some embodiments, the numerical value is 11-15. In some embodiments, the numerical value is 16-20. In some embodiments, the numerical value is 21-25. In some embodiments, the numerical value is 26-30. In some embodiments, the numerical value is 31-35. In some embodiments, the numerical value is 36-40. In some embodiments, the numerical value is 41-45. In some embodiments, the numerical value is 46-50. In some embodiments, the numerical value is 51-55. In some embodiments, the numerical value is 56-60. In some embodiments, the numerical value is 1-60.
  • the baseline MADRS score comprises a baseline subscore such as a baseline apparent sadness score, a baseline reported sadness score, a baseline inner tension score, a baseline reduced sleep score, a baseline reduced appetite score, a baseline concentration difficulties score, a baseline lassitude score, a baseline inability to feel score, a baseline pessimistic thoughts score, or a baseline suicidal Attorney Docket No.54462-754.601 thoughts score.
  • Each baseline subscore may comprise a numerical value of 0, 1, 2, 3, 4, 5, or 6, or a range of such numerical values.
  • the baseline MADRS score comprises a numerical value at or above a threshold numerical value that is indicative of a depressive disorder.
  • the subject may be depressed prior to treatment and have a baseline MADRS score of 7-60.
  • the subject may have mild depression prior to treatment and have a baseline MADRS score of 7-19.
  • the subject may have moderate depression prior to treatment and have a baseline MADRS score of 20-34.
  • the subject may have severe depression prior to treatment and have a baseline MADRS score over 34.
  • one or more of the baseline subscores comprise a numerical value at or above a threshold numerical value that is indicative of the depressive disorder.
  • the baseline measurement comprises a baseline Hamilton Depression Rating Scale (HDRS) score.
  • the HRSD typically includes a multiple item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery.
  • the questionnaire is usually designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms.
  • the subject is usually rated by a clinician on 17 to 29 items (depending on version) scored either on a 3-point or 5-point Likert-type scale.
  • the HDRS includes 17 items (HDRS17).
  • Other variations may be used, such as those that include more than 17 items.
  • up to 29 items may be used in some cases (HDRS29).
  • a score of 0–7 is typically considered to be normal while a score of 20 or higher may indicate moderate or severe depression.
  • the baseline HDRS score comprises a numerical value such as a number of points.
  • the numerical value is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or a range defined by any two of the aforementioned numerical values.
  • the numerical value is 1-5.
  • the numerical value is 6-10.
  • the numerical value is 11-15.
  • the numerical value is 16-20. In some embodiments, the numerical value is 21-25.
  • the numerical value is 26-30. In some embodiments, the numerical value is 31-35. In some embodiments, the numerical value is 36-40. In some embodiments, the numerical value is 41-45. In some embodiments, the numerical value is 46-50. In some embodiments, the numerical value is 51 or 52. In some embodiments, the numerical value is 1-50. In some embodiments, the numerical value is 1-52.
  • the baseline HDRS score comprises a baseline subscore such as a baseline depressed mood score, a baseline feelings of guilt score, a baseline suicide score, a baseline insomnia early in the night score, a baseline insomnia in the middle of the night score, a baseline insomnia in early hours of the morning score, a baseline work and activities score, a baseline retardation score, a baseline agitation score, a baseline anxiety psychic score, a baseline anxiety somatic score, a baseline somatic symptoms of gastrointestinal score, a baseline general somatic score, a baseline genital symptoms score, a baseline hypochondriasis score, a baseline loss of weight score, or a baseline insight score.
  • a baseline subscore such as a baseline depressed mood score, a baseline feelings of guilt score, a baseline suicide score, a baseline insomnia early in the night score, a baseline insomnia in the middle of the night score, a baseline insomnia in early hours of the morning score, a baseline work and activities score, a baseline retardation score, a baseline agitation score,
  • Baseline subscores may comprise a numerical value of 0, 1, or 2, or a range of such numerical values.
  • Baseline subscores may comprise a numerical value of 0, 1, 2, 3, or 4, or Attorney Docket No.54462-754.601 a range of such numerical values.
  • the baseline HDRS score comprises a numerical value at or above a threshold numerical value that is indicative of a depressive disorder. For example, a HDRS score of 20 or higher may be indicative of moderate to severe depression.
  • the subject is depressed prior to treatment and has an HDRS score above 19.
  • the subject is at least mildly depressed prior to treatment and has an HDRS score above 7.
  • the baseline subscore comprises a numerical value at or above a threshold numerical value that is indicative of the depressive disorder.
  • the baseline measurement is a baseline anxiety measurement.
  • the baseline anxiety measurement may include a baseline assessment of a sign or symptom of anxiety (e.g., a baseline anxiety sign or symptom). Examples of signs or symptoms of anxiety include stress (e.g., stress that's out of proportion to the impact of an event), worry (for example, inability to set aside a worry), or restlessness.
  • the symptom of anxiety includes one or more behavioral symptoms such as hypervigilance, irritability, or restlessness.
  • the symptom of anxiety includes one or more cognitive symptoms such as lack of concentration, racing thoughts, or unwanted thoughts.
  • the symptom of anxiety includes one or more whole body symptoms such as fatigue or sweating.
  • the symptoms of anxiety include any of excessive worry, fear, feeling of impending doom, insomnia, nausea, palpitations, or trembling.
  • the symptom includes one or more panic attacks.
  • the baseline assessment may include an amount, frequency, duration, or intensity of the anxiety or symptoms of anxiety.
  • the baseline assessment may include an amount of time since experiencing the anxiety or symptoms.
  • the baseline assessment may include a frequency of experiencing the anxiety or symptoms.
  • the baseline measurement is a baseline eating disorder measurement.
  • the baseline measurement is a baseline eating disorder sign or symptom.
  • Examples of eating disorders include anorexia, bulimia, binge eating disorder, pica, rumination, or avoidant eating disorder.
  • the eating disorder includes anorexia nervosa.
  • the eating disorder includes bulimia.
  • the eating disorder includes binge eating.
  • the eating disorder includes pica.
  • the baseline eating disorder measurement may include a baseline assessment of a sign or symptom of eating disorder (e.g., a baseline eating disorder sign or symptom).
  • Some examples of symptoms of an eating disorder comprising anorexia nervosa include being considerably underweight compared with people of similar age and height, very restricted eating patterns, an intense fear of gaining weight or persistent behaviors to avoid gaining weight despite being underweight, a relentless pursuit of thinness and unwillingness to maintain a healthy weight, a heavy influence of body weight or perceived body shape on self-esteem, a distorted body image, or denial of being seriously underweight.
  • the baseline assessment may include an amount, frequency, duration, or intensity of the engaging in the eating disorder or experiencing symptoms of the eating disorder.
  • the baseline assessment may include an amount of time since engaging in the eating disorder or experiencing symptoms of the eating disorder.
  • the baseline assessment may include a frequency of engaging in the eating disorder or experiencing symptoms of the eating disorder.
  • the baseline measurement is a baseline substance-use measurement.
  • the baseline substance-use measurement includes a baseline determination of a level of addiction to an addictive substance.
  • addictive substances include alcohol, antianxiety drugs, sedative drugs, caffeine, cannabis (e.g., including marijuana or synthetic cannabinoids), hallucinogens (e.g., LSD, phencyclidine, or psilocybin), inhalants (e.g., paint thinner or some glues), opioids (e.g., fentanyl, morphine, or oxycodone), stimulants (e.g., amphetamines or cocaine), tobacco, or anabolic steroids.
  • addictive substances include alcohol, antianxiety drugs, sedative drugs, caffeine, cannabis (e.g., including marijuana or synthetic cannabinoids), hallucinogens (e.g., LSD, phencyclidine, or psilocybin), inhalants (e.g., paint thinner or some glues), opioids (e.g.
  • the baseline determination of a level of addiction to an addictive substance may include a questionnaire or assessment.
  • the baseline determination of a level of addiction to an addictive substance may include an amount of time since ingesting the addictive substance.
  • the baseline determination of a level of addiction to an addictive substance may include a frequency of ingesting the addictive substance.
  • the baseline assessment may include an amount, frequency, duration, or intensity of the engaging in the substance-use disorder or experiencing symptoms of the substance-use disorder.
  • the baseline assessment may include an amount of time since engaging in the substance-use disorder or experiencing symptoms of the substance-use disorder.
  • the baseline assessment may include a frequency of engaging in the substance-use disorder or experiencing symptoms of the substance-use disorder.
  • the baseline assessment may include signs or symptoms of the substance-use disorder.
  • the baseline measurement comprises a baseline post-traumatic stress disorder (PTSD) measurement.
  • the baseline PTSD measurement includes a baseline determination of the level of severity of PTSD.
  • the baseline assessment of a sign or symptom of PTSD may include the number of signs or symptoms of PTSD.
  • the baseline determination of the level of severity of PTSD may include the time since last experiencing a PTSD flashback (e.g., reliving the traumatic event as if it were happening again), nightmare, or severe anxiety.
  • the baseline assessment may include a frequency in PTSD related flashbacks, nightmares, or severe anxiety episodes.
  • the baseline assessment may include a severity of a sign or symptom of PTSD.
  • the baseline assessment may include a frequency of a sign or symptom of PTSD.
  • Exemplary signs and symptoms of PTSD may include intrusive memories (e.g., recurrent, unwanted distressing memories of a traumatic event, severe emotional distress or physical reactions to something that reminiscent of the traumatic event, attempts to avoid thinking or talking about the traumatic event, avoiding places, activities or people pronounced of the traumatic event, thoughts of hopelessness, memory problems, difficulty maintaining close relationships, and feeling a lack of interest in activities that were once enjoyed.
  • the baseline measurement comprises a baseline bipolar disorder measurement.
  • the baseline bipolar disorder measurement is a sign or symptom of bipolar disorder.
  • the baseline assessment of a sign or symptom of bipolar disorder may include a frequency of a sign or symptom of bipolar disorder.
  • the baseline assessment of a sign or symptom of bipolar disorder may include a severity of a sign or symptom of bipolar disorder.
  • the baseline assessment Attorney Docket No.54462-754.601 of a sign or symptom of bipolar disorder may include the number of signs or symptoms of bipolar disorder.
  • Exemplary signs and symptoms of bipolar disorder include any of the bipolar signs and symptoms disclosed herein, including, manic episodes (e.g., experiencing feelings of increased activity, energy, or agitation, an exaggerated sense of well-being and self-confidence, a decreased need for sleep, racing thoughts, distractibility, and a decreased ability to control impulses), and major depressive episodes (e.g., experiencing a depressed mood, marked loss of interest of feelings of pleasure, fatigue or loss of energy, feelings of guilt or worthlessness, and a decreased ability to think or concentrate).
  • the baseline measurement comprises a baseline schizophrenia measurement.
  • the baseline schizophrenia measurement is a sign or symptom of schizophrenia.
  • the baseline assessment of a sign or symptom of schizophrenia may include a frequency of a sign or symptom of schizophrenia.
  • the baseline assessment of a sign or symptom of schizophrenia may include a severity of a sign or symptom of schizophrenia.
  • the baseline assessment of a sign or symptom of schizophrenia may include the number of signs or symptoms of schizophrenia.
  • Exemplary signs and symptoms of schizophrenia may include delusions, hallucinations, disorganized thoughts and speech, disorganized or abnormal motor behavior, and negative symptoms (e.g., social withdrawal, anhedonia, avolition, decreased sense of purpose, lack of interest in activities, flat affect, lack of eye contact, and physical inactivity.
  • the baseline measurement comprises a baseline psychosis measurement.
  • the baseline psychosis measurement is a baseline sign or symptom of psychosis (e.g., baseline psychosis sign or symptom).
  • the baseline assessment of a sign or symptom of psychosis may include a frequency of a sign or symptom of psychosis.
  • the baseline assessment of a sign or symptom of psychosis may include a severity of a sign or symptom of psychosis.
  • the baseline assessment of a sign or symptom of psychosis may include the number of signs or symptoms of psychosis.
  • Exemplary signs and symptoms of psychosis may include difficulty concentrating, depressed mood, anxiety, excessive suspiciousness, delusions, and hallucinations.
  • the baseline measurement comprises a baseline measurement of a neurological disorder.
  • Non-limiting examples of baseline measurements of neurological disorders include a baseline cognitive function measurement, a baseline amyloid plaque measurement, a baseline tau accumulation measurement, a baseline beta-amyloid 42 measurement, a baseline beta-amyloid 40 measurement, a baseline beta-amyloid 42 to plasma beta-amyloid 40 ratio measurement, a baseline tau measurement, a baseline phospho-tau measurement, a baseline neurofilament light (NfL) measurement, a baseline glial fibrillary acidic protein (GFAP) measurement, a baseline alpha-synuclein measurement, a baseline Lewy body measurement,.
  • a baseline cognitive function measurement a baseline amyloid plaque measurement, a baseline tau accumulation measurement, a baseline beta-amyloid 42 measurement, a baseline beta-amyloid 40 measurement, a baseline beta-amyloid 42 to plasma beta-amyloid 40 ratio measurement, a baseline tau measurement, a baseline phospho-tau measurement, a baseline neurofilament light (NfL) measurement, a baseline glial fibrill
  • baseline measurements include a baseline measurement of headache signs and/or symptoms, a baseline measurement of migraine symptoms and/or signs, a baseline measurement of chronic pain symptoms and/or signs, a baseline measurement of fibromyalgia symptoms and/or signs, a baseline measurement of chronic fatigue syndrome (ME) symptoms and/or signs, a baseline measurement of chronic traumatic encephalopathy Attorney Docket No.54462-754.601 symptoms and/or signs, a baseline measurement of traumatic brain injury symptoms and/or signs, and a baseline measurement of motor neuron disease (e.g., ALS) symptoms and/or signs.
  • the baseline measurement is a baseline amyloid plaque measurement.
  • the baseline amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement.
  • the baseline amyloid plaque measurement includes a baseline concentration or amount.
  • the baseline amyloid plaque measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • PET positron emission tomography
  • the baseline amyloid plaque measurement may be performed on a biopsy.
  • the baseline amyloid plaque measurement may be performed using a spinal tap (for example, when the baseline amyloid plaque measurement includes a baseline cerebrospinal fluid (CSF) amyloid plaque measurement).
  • the baseline amyloid plaque measurement is obtained by an assay such as an immunoassay.
  • the baseline beta amyloid plaque measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.
  • the baseline measurement is a baseline beta-amyloid 42 measurement.
  • the baseline beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement.
  • the baseline beta-amyloid 42 measurement may include a plasma beta-amyloid 42 measurement.
  • the baseline beta-amyloid 42 measurement includes a baseline concentration or amount.
  • the baseline beta-amyloid 42 measurement may be performed on a biopsy.
  • the baseline ratio of beta-amyloid 42 measurement may be performed on a blood sample.
  • the baseline beta- amyloid 42 measurement may be performed using a spinal tap (for example, when the baseline beta- amyloid 42 measurement includes a baseline CSF beta-amyloid 42 measurement).
  • the baseline beta-amyloid 42 measurement is obtained by an assay such as an immunoassay.
  • the baseline beta-amyloid 42 measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.
  • the baseline measurement is a baseline beta-amyloid 40 measurement.
  • the baseline beta-amyloid 40 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 40 measurement.
  • the baseline beta-amyloid 40 measurement may include a plasma beta-amyloid 40 measurement.
  • the baseline beta-amyloid 40 measurement includes a baseline concentration or amount.
  • the baseline beta-amyloid 40 measurement may be performed on a biopsy.
  • the baseline ratio of beta-amyloid 40 measurement may be performed on a blood sample.
  • the baseline beta- amyloid 40 measurement may be performed using a spinal tap (for example, when the baseline beta- amyloid 40 measurement includes a baseline CSF beta-amyloid 40 measurement).
  • the baseline beta-amyloid 40 measurement is obtained by an assay such as an immunoassay.
  • the baseline beta-amyloid 40 measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.
  • the baseline measurement is a baseline ratio of beta-amyloid 42 to beta- amyloid 40 measurement.
  • the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement may include a cerebrospinal fluid (CSF) ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • CSF cerebrospinal fluid
  • the Attorney Docket No.54462-754.601 baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement may include a plasma ratio of beta- amyloid 42 to beta-amyloid 40 measurement.
  • the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement includes a baseline concentration or amount.
  • the baseline ratio of beta- amyloid 42 to beta-amyloid 40 measurement may be performed on a biopsy.
  • the baseline ratio of beta- amyloid 42 to beta-amyloid 40 measurement may be performed on a blood sample.
  • the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement may be performed using a spinal tap (for example, when the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement includes a baseline CSF ratio of beta-amyloid 42 to beta-amyloid 40 measurement).
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement is obtained by an assay such as an immunoassay.
  • the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.
  • the baseline measurement is a baseline tau measurement.
  • the baseline tau measurement includes a baseline concentration or amount.
  • the baseline tau measurement may be performed on a biopsy.
  • the baseline tau measurement is obtained by an assay such as an immunoassay.
  • the baseline tau measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • PET positron emission tomography
  • the baseline beta tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the baseline tau measurement is a baseline central nervous system (CNS) tau measurement.
  • the baseline tau measurement may include a baseline total tau measurement.
  • the baseline tau measurement may include a baseline unphosphorylated tau measurement.
  • the baseline tau measurement may include a baseline phosphorylated tau (phospho-tau) measurement.
  • the baseline tau measurement is a baseline tau accumulation measurement.
  • the baseline tau measurement is a baseline CNS tau accumulation measurement.
  • the baseline CNS tau accumulation measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the baseline tau measurement may include a cerebrospinal fluid (CSF) or plasma tau measurement.
  • CSF cerebrospinal fluid
  • the baseline tau measurement may be performed using a spinal tap (for example, when the baseline tau measurement includes a baseline CSF tau measurement).
  • the baseline tau measurement may be performed on a blood sample.
  • the baseline CSF tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the baseline tau measurement may include a baseline phospho-tau measurement.
  • the baseline phospho-tau measurement may be performed on a blood sample.
  • the baseline phospho-tau measurement may be performed using a spinal tap (for example, when the baseline phospho-tau measurement includes a baseline CSF phospho-tau measurement).
  • the baseline phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau.
  • the baseline phospho-tau measurement may include a phospho-tau/tau ratio.
  • the baseline phospho-tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the baseline measurement is a baseline neurofilament light chain (NfL) measurement.
  • the baseline NfL measurement includes a baseline CSF or plasma NfL measurement.
  • the baseline NfL measurement may be a baseline CSF NfL measurement.
  • the baseline NfL measurement may be a baseline plasma NfL measurement.
  • the NfL measurement may include a concentration or an amount.
  • the baseline NfL measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the baseline measurement is a baseline glial fibrillary acidic protein (GFAP) measurement.
  • the baseline GFAP measurement includes a baseline CSF or plasma GFAP measurement.
  • the baseline GFAP measurement may be a baseline CSF GFAP measurement.
  • the baseline GFAP measurement may be a baseline plasma GFAP measurement.
  • the GFAP measurement may include a concentration or an amount.
  • the baseline GFAP measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or cognitive impairment.
  • the baseline measurement is a baseline alpha-synuclein measurement.
  • the baseline alpha-synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement.
  • the baseline alpha-synuclein measurement includes a baseline concentration or amount.
  • the baseline alpha-synuclein measurement may be performed on a biopsy.
  • the baseline alpha-synuclein measurement may be performed using a spinal tap (for example, when the baseline alpha-synuclein measurement includes a baseline CSF alpha-synuclein measurement).
  • the baseline alpha-synuclein measurement is obtained by an assay such as an immunoassay.
  • the baseline alpha-synuclein measurement may be indicative of a neurodegenerative disease such as Parkinson’s disease.
  • the baseline alpha-synuclein measurement may be indicative of dementia.
  • the baseline measurement is a baseline Lewy body measurement.
  • the baseline Lewy body measurement may include a central nervous system (CNS) Lewy body measurement.
  • CNS central nervous system
  • the baseline Lewy body measurement includes a baseline concentration or amount.
  • the baseline Lewy body measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • PET positron emission tomography
  • the baseline beta Lewy body measurement may be indicative of dementia.
  • the baseline measurement is a baseline cognitive function measurement.
  • the baseline cognitive function measurement may be obtained directly from the subject.
  • the subject may be administered a test.
  • the test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or Mini-Cog.
  • the test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial ability, behavior, mood, orientation, or attention.
  • the baseline cognitive function measurement may include a score.
  • the baseline cognitive function measurement may be indicative of mild cognitive impairment, or of severe cognitive impairment.
  • the baseline cognitive function measurement may be indicative of a neurological disorder.
  • the baseline measurement is a baseline headache measurement.
  • the baseline headache measurement is a baseline headache sign or symptom measurement.
  • the baseline headache measurement is a baseline migraine (e.g., with aura or without aura) measurement.
  • the baseline headache measurement is a frequency of a headache sign or symptom measurement.
  • the baseline headache measurement is a severity of a headache sign or symptom measurement. In some embodiments, the baseline headache measurement is a number of headache signs or symptoms. Exemplary signs and symptoms of headaches include pain (e.g., deep and constant) in the cheekbones, forehead, bridge of the nose, the cranium, or the back of the neck, aura, photophobia, phonophobia, and emesis.
  • the baseline measurement is a baseline chronic pain measurement. In some embodiments, baseline chronic pain measurement is a baseline fibromyalgia measurement. In some embodiments, the baseline chronic pain measurement is a baseline chronic pain sign or symptom measurement.
  • the baseline chronic pain measurement is a frequency of a chronic pain sign or symptom measurement. In some embodiments, the baseline chronic pain measurement is a severity of a chronic pain sign or symptom measurement. In some embodiments, the baseline chronic pain measurement is a number of chronic pain signs or symptoms. Exemplary signs and symptoms of fibromyalgia include muscular pain, fatigues, depression, anxiety, sleeplessness, headache, and difficulty concentrating. Exemplary chronic pain disorders include postsurgical pain, post-trauma pain, low back pain, cancer pain, arthritis pain, muscular pain, and neuropathic pain (e.g., diabetic neuropathy). [00401] In some embodiments, the baseline measurement is a baseline chronic fatigue syndrome (also referred to as myalgic encephalomyelitis) measurement.
  • myalgic encephalomyelitis also referred to as myalgic encephalomyelitis
  • the baseline chronic fatigue syndrome measurement is a baseline chronic fatigue syndrome sign or symptom measurement. In some embodiments, the baseline chronic fatigue syndrome measurement is a frequency of a headache sign or symptom measurement. In some embodiments, the baseline chronic fatigue syndrome measurement is a severity of a chronic fatigue syndrome sign or symptom measurement. In some embodiments, the baseline chronic fatigue syndrome measurement is a number of chronic fatigue syndrome signs or symptoms. Exemplary signs and symptoms of chronic fatigue syndrome include extreme fatigue that lasts for extended periods of time (e.g., for at least six months) that cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., joint or muscular), malaise, forgetfulness, anxiety, and depression.
  • extreme fatigue that lasts for extended periods of time (e.g., for at least six months) that cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., joint or muscular), malaise, forgetfulness, anxiety, and depression.
  • the baseline measurement is a baseline chronic traumatic encephalopathy measurement.
  • the baseline chronic traumatic encephalopathy measurement is a baseline chronic traumatic encephalopathy sign or symptom measurement.
  • the baseline chronic traumatic encephalopathy measurement is a number of chronic traumatic encephalopathy signs or symptoms measurement. Exemplary signs and symptoms of chronic traumatic encephalopathy include cognitive impairment, dementia, agitation, disorientation, playful or unusual behavior, depression, suicidal behavior or threats of self-injury, and movement disorders.
  • the baseline measurement is a baseline traumatic brain injury measurement.
  • the baseline traumatic brain injury measurement is a baseline traumatic brain injury sign or symptom measurement.
  • the baseline traumatic brain Attorney Docket No.54462-754.601 injury measurement is a number of traumatic brain injury signs or symptoms measurement. Exemplary signs and symptoms of traumatic brain injury include cognitive deficits, motor deficits, sensory or perceptual deficits, communication or language deficits, functional deficits, social difficulties, regulatory disturbances, personality changes and mood disorders, and traumatic epilepsy.
  • the baseline measurement is a baseline motor neuron disease measurement. In some embodiments, the baseline motor neuron disease measurement is an amyotrophic lateral sclerosis (ALS) measurement. In some embodiments, the baseline motor neuron disease measurement is a baseline motor neuron disease sign or symptom measurement.
  • ALS amyotrophic lateral sclerosis
  • the baseline motor neuron disease measurement is a frequency of a motor neuron disease sign or symptom measurement. In some embodiments, the baseline motor neuron disease measurement is a severity of a motor neuron disease sign or symptom measurement. In some embodiments, the baseline motor neuron disease measurement is a number of motor neuron disease signs or symptoms. Exemplary forms of motor neuron diseases include progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), ALS, and primary lateral sclerosis (PLS). Exemplary signs and symptoms of motor neuron diseases include motor control difficulties (e.g., difficulty walking or completing normal daily activities), muscular weakness, slurred speech, difficulty swallowing, and muscle cramps and twitching (e.g., in the arms, shoulders, or tongue).
  • PBP progressive bulbar palsy
  • PMA progressive muscular atrophy
  • ALS ALS
  • PLS primary lateral sclerosis
  • Exemplary signs and symptoms of motor neuron diseases include motor control difficulties (e.g., difficulty walking or completing normal daily activities), muscular weakness,
  • the baseline measurement is a baseline level of fibrinogen. In some embodiments, the baseline measurement is a baseline level of circulating fibrinogen. The baseline measurement may include a baseline fibrin measurement. Where a baseline fibrinogen level or measurement is described, a baseline fibrin level or measurement may also be contemplated. [00406] In some embodiments, the baseline measurement is a baseline clotting or coagulation measurement. In some embodiments, the baseline measurement is a baseline clotting time measurement. In some embodiments, the baseline measurement is a baseline prothrombin time (PT). In some embodiments, the baseline measurement is a baseline International Normalized Ratio (INR).
  • INR International Normalized Ratio
  • the baseline measurement is a baseline activated partial thromboplastin time (aPTT).
  • the disorder e.g., baseline measurement
  • the disorder may be diagnosed or measured with the use of a questionnaire or a scoring system.
  • the disorder is diagnosed according to DSM-5 criteria.
  • the disorder is diagnosed by a healthcare professional (e.g., physician or the like).
  • Baseline measurements may include a baseline FGG protein measurement, or a baseline FGG mRNA measurement.
  • Baseline measurements may include any one or more of the baseline measurements disclosed herein.
  • the baseline measurement is obtained directly from the subject.
  • the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device. In some embodiments, the baseline measurement is obtained invasively using an imaging device. Attorney Docket No.54462-754.601 [00411] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject.
  • an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay
  • the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR. [00412] In some embodiments, the baseline measurement is a baseline FGG protein measurement. In some embodiments, the baseline FGG protein measurement comprises a baseline FGG protein level. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample weight. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per sample volume. In some embodiments, the baseline FGG protein level is indicated as a mass or percentage of FGG protein per total protein within the sample.
  • the baseline FGG protein measurement is a baseline tissue FGG protein measurement.
  • the baseline FGG protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.
  • the baseline FGG protein level is measured in the whole body.
  • the baseline FGG protein level is measured in the brain.
  • the baseline FGG protein level is measured in the liver.
  • the baseline FGG protein level is measured in the blood. [00413]
  • the baseline measurement is a baseline FGG mRNA measurement.
  • the baseline FGG mRNA measurement comprises a baseline FGG mRNA level.
  • the baseline FGG mRNA level is measured in the liver. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample weight. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per sample volume. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total mRNA within the sample. In some embodiments, the baseline FGG mRNA level is indicated as an amount or percentage of FGG mRNA per total nucleic acids within the sample. In some embodiments, the baseline FGG mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample.
  • the baseline FGG mRNA measurement is a baseline tissue FGG mRNA measurement.
  • the baseline FGG mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay.
  • the PCR comprises quantitative PCR (qPCR).
  • the PCR comprises reverse transcription of the FGG mRNA.
  • Some embodiments of the methods described herein include obtaining a sample from a subject.
  • the baseline measurement is obtained in a sample obtained from the subject.
  • the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein.
  • a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.
  • the sample is obtained from the subject in a fasted state. In some embodiments, the sample is obtained from the subject after an overnight fasting period. In some embodiments, the sample is obtained from the subject in a fed state.
  • the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample.
  • the blood is fractionated or centrifuged.
  • the sample comprises plasma.
  • the sample is a plasma sample.
  • a blood sample may be a plasma sample.
  • the sample comprises serum.
  • the sample is a serum sample.
  • a blood sample may be a serum sample.
  • the sample is a CSF sample.
  • the sample includes a CSF sample.
  • the sample is a CNS sample.
  • the sample includes a CNS sample.
  • the sample comprises a CNS sample.
  • the sample comprises a tissue.
  • the sample is a tissue sample.
  • the tissue comprises liver or brain tissue.
  • the baseline FGG mRNA measurement, or the baseline FGG protein measurement may be obtained in a brain or liver sample obtained from the patient.
  • the tissue comprises neural tissue.
  • the tissue comprises neuronal tissue.
  • the tissue comprises neurons.
  • the tissue comprises glial cells.
  • the tissue comprises epithelial cells.
  • the tissue comprises liver tissue. The liver may include hepatocytes.
  • the tissue comprises brain tissue.
  • the sample comprises CSF fluid. [00417]
  • the sample includes cells. In some embodiments, the sample comprises a cell.
  • the cell comprises a liver cell (e.g., hepatocyte), or a brain cell.
  • the cell is a liver cell.
  • the liver cell is a hepatocyte.
  • the cell is a brain cell.
  • the cell is a neuron.
  • the cell is a glial cell.
  • the cell is an epithelial cell.
  • the cell is a vasculature cell.
  • the composition or administration of the composition affects a measurement such as mental disorder (e.g., psychiatric disorder or neurological disorder) measurement.
  • the composition or administration of the composition affects a measurement such as psychiatric measurement (e.g., a Montgomery-Asberg Depression Rating Scale (MADRS) score, a Hamilton Depression Rating Scale (HDRS) score, anxiety signs or symptoms, eating disorder signs or symptoms, substance-use disorder signs or symptoms, post-traumatic stress disorder (PTSD) signs or symptoms, bipolar disorder signs or symptoms, schizophrenia signs or symptoms, or psychosis signs or symptoms).
  • a measurement such as psychiatric measurement, relative to the baseline measurement.
  • administration of the composition affects a measurement of an aspect in any of Tables 1A- 1C and 2A-2B.
  • the measurement may include a fibrinogen measurement, a fibrin measurement, a FGG mRNA measurement, or a FGG protein measurement.
  • the measurement may include a clotting measurement, a prothrombin time (PT) measurement, an International Normalized Ratio (INR) measurement, or a activated partial thromboplastin time (aPTT) measurement.
  • PT prothrombin time
  • ILR International Normalized Ratio
  • aPTT activated partial thromboplastin time
  • the composition or administration of the composition affects a neurological measurement such as a cognitive function measurement, an amyloid plaque measurement, a tau accumulation measurement, a beta-amyloid 42 measurement, a beta-amyloid 40 measurement, the ratio of beta-amyloid 42 to beta-amyloid 40 measurement, a tau measurement, a phospho-tau measurement (such a p-tau217), a neurofilament light chain (NfL) measurement, a glial fibrillary acidic protein (GFAP) measurement, an alpha-synuclein measurement, a Lewy body measurement, headache signs or symptoms, migraine signs or symptoms, chronic pain signs or symptoms, fibromyalgia signs or symptoms, chronic fatigue (ME) signs or symptoms, chronic traumatic encephalopathy signs or symptoms, traumatic brain injury signs or symptoms, motor neuron disease signs or symptoms, or ALS signs or symptoms).
  • a neurological measurement such as a cognitive function measurement, an amyloid plaque measurement, a tau accumulation measurement, a beta-amyloid 42
  • the composition or administration of the composition affects a measurement, such as neurological measurement, relative to the baseline measurement.
  • the measurement indicates that the disorder has been treated. In some embodiments, the measurement indicates that the severity of the disorder has decreased. In some embodiments, the measurement indicates that the severity of a sign or symptom of the disorder has decreased. In some embodiments, the measurement indicates that the frequency of a sign or symptom of the disorder has decreased. [00421] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject.
  • the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated. [00422] In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein.
  • the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay.
  • the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay.
  • the measurement is obtained by PCR.
  • the measurement is obtained by histology.
  • the measurement is obtained by observation.
  • additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample.
  • the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition.
  • the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition.
  • the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition.
  • the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.
  • the composition reduces the measurement relative to the baseline measurement.
  • an adverse phenotype of a psychiatric or neurological disorder may be reduced upon administration of the composition.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured directly in the subject after administering the composition to the subject.
  • the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement.
  • the measurement is decreased by about 10% or more, relative to the baseline measurement.
  • the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement.
  • the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the composition increases the measurement relative to the baseline measurement.
  • a protective psychiatric or neurological phenotype may be increased upon administration of the composition.
  • the increase is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the increase is measured directly in the subject after administering the composition to the subject.
  • the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement.
  • the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement.
  • the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement.
  • the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a Montgomery-Asberg Depression Rating Scale (MADRS) score.
  • the MADRS score comprises a numerical value such as a number of points.
  • the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 5556, 57, 58, 59, or 60, or a range defined by any two of the aforementioned numerical values.
  • the numerical value is 0.
  • the numerical value is 1-5.
  • the numerical value is 6-10.
  • the numerical value is 11-15.
  • the numerical value is 16-20.
  • the numerical value is 21-25.
  • the numerical value is 26-30. In some embodiments, the numerical value is 31-35. In some embodiments, the numerical value is 36-40. In some embodiments, the numerical value is 41-45. In some embodiments, the numerical value is 46-50. In some embodiments, the numerical value is 51-55. In some embodiments, the numerical value is 56-60. In some embodiments, the numerical value is 0-60.
  • the MADRS score comprises a subscore such as an apparent sadness score, a reported sadness score, an inner tension score, a reduced sleep score, a reduced appetite score, a concentration difficulties score, a lassitude score, an inability to feel score, a pessimistic thoughts score, or a suicidal thoughts score.
  • Each subscore may comprise a numerical value of 0, 1, 2, 3, 4, 5, or 6, or a range of such numerical values.
  • the MADRS score comprises a numerical value below a threshold numerical value that is indicative of a depressive disorder.
  • the subscore comprises a numerical value below a threshold numerical value that is indicative of a depressive disorder.
  • the composition reduces the MADRS score relative to the baseline MADRS score. In some embodiments, the reduced MADRS score by observing and/or questioning the subject after administering the composition to the subject.
  • the MADRS score is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MADRS score. In some embodiments, the MADRS score is decreased by about 10% or more, relative to the baseline MADRS score. In some embodiments, the MADRS score is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline MADRS score. In some embodiments, the MADRS score is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline MADRS score.
  • the MADRS score is decreased by no more than about 10%, relative to the baseline MADRS score. In some embodiments, the MADRS score is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline MADRS score. In some embodiments, the MADRS score is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the MADRS score is decreased by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 5556, 57, 58, 59, or 60 points, relative to the baseline MADRS score, or by a range of points defined by any two of the aforementioned numbers of points relative to the baseline MADRS score.
  • the MADRS score is decreased by 1-5 points. In some embodiments, the MADRS score is decreased by 6-10 points.
  • the MADRS score is decreased by 11-15 points. In some embodiments, the MADRS score is decreased by 16-20 points. In some embodiments, the MADRS score is decreased by 21-25 points. In some embodiments, the MADRS score is decreased by 26-30 points. In some embodiments, the MADRS score is decreased by 31-35 points. In some embodiments, the MADRS score is decreased by 36-40 points. In some embodiments, the MADRS score is decreased by 41-45 points. In some embodiments, the MADRS score is decreased by 46-50 points. In some embodiments, the MADRS score is decreased by 51-55 points. In some embodiments, the MADRS score is decreased by 56-60 points.
  • the MADRS score of the subject is decreased such that the MADRS score of the subject changes from severe depression to mild or moderate depression, or to normal non-depressed symptomology.
  • the MADRS score of the subject may be below 35 following treatment.
  • the MADRS score changes from moderate depression to mild depression, or to normal non-depressed symptomology.
  • the MADRS score of the subject may be below 20 following treatment.
  • the MADRS Attorney Docket No.54462-754.601 score changes from mild depression to normal non-depressed symptomology.
  • the MADRS score of the subject may be below 7 following treatment.
  • the measurement is a Hamilton Depression Rating Scale (HDRS) score.
  • the HDRS score comprises a numerical value such as a number of points.
  • the numerical value is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or a range defined by any two of the aforementioned numerical values.
  • the numerical value is 0.
  • the numerical value is 1-5.
  • the numerical value is 6-10.
  • the numerical value is 11-15.
  • the numerical value is 16-20. In some embodiments, the numerical value is 21-25. In some embodiments, the numerical value is 26-30. In some embodiments, the numerical value is 31-35. In some embodiments, the numerical value is 36-40. In some embodiments, the numerical value is 41-45. In some embodiments, the numerical value is 46-50. In some embodiments, the numerical value is 0-50.
  • the HDRS score comprises a subscore such as a depressed mood score, a feelings of guilt score, a suicide score, a insomnia early in the night score, a insomnia in the middle of the night score, a insomnia in early hours of the morning score, a work and activities score, a retardation score, a agitation score, an anxiety psychic score, an anxiety somatic score, a somatic symptoms of gastrointestinal score, a general somatic score, a genital symptoms score, a hypochondriasis score, a loss of weight score, or an insight score.
  • Subscores may comprise a numerical value of 0, 1, or 2, or a range of such numerical values.
  • Subscores may comprise a numerical value of 0, 1, 2, 3, or 4, or a range of such numerical values.
  • the HDRS score comprises a numerical value below a threshold numerical value that is indicative of a depressive disorder. For example, a score of below 20 may indicate a lack of moderate or severe depression.
  • the subscore comprises a numerical value below a threshold numerical value that is indicative of the depressive disorder.
  • the composition reduces the HDRS score relative to the baseline HDRS score. In some embodiments, the reduced HDRS score by observing and/or questioning the subject after administering the composition to the subject.
  • the HDRS score is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline HDRS score. In some embodiments, the HDRS score is decreased by about 10% or more, relative to the baseline HDRS score. In some embodiments, the HDRS score is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline HDRS score. In some embodiments, the HDRS score is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline HDRS score.
  • the HDRS score is decreased by no more than about 10%, relative to the baseline HDRS score. In some embodiments, the HDRS score is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline HDRS score. In some embodiments, the HDRS score is Attorney Docket No.54462-754.601 decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the HDRS score is decreased by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4041, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 56, 57, 58, 59, or 60 points, relative to the baseline HDRS score, or by a range of points defined by any two of the aforementioned numbers of points relative to the baseline HDRS score.
  • the HDRS score is decreased by 1-5 points.
  • the HDRS score is decreased by 6-10 points.
  • the HDRS score is decreased by 11-15 points.
  • the HDRS score is decreased by 16-20 points. In some embodiments, the HDRS score is decreased by 21-25 points. In some embodiments, the HDRS score is decreased by 26-30 points. In some embodiments, the HDRS score is decreased by 31-35 points. In some embodiments, the HDRS score is decreased by 36-40 points. In some embodiments, the HDRS score is decreased by 41-45 points. In some embodiments, the HDRS score is decreased by 46-50 points. In some embodiments, the HDRS score is decreased by 51-55 points. In some embodiments, the HDRS score is decreased by 56-60 points.
  • the HDRS score of the subject is decreased such that the HDRS score of the subject changes from severe depression to mild or moderate depression, or to normal non-depressed symptomology. In some embodiments, the HDRS score changes from moderate depression to mild depression, or to normal non-depressed symptomology. For example, the HDRS score of the subject may be below 20 following treatment. In some embodiments, the HDRS score changes from mild depression to normal non-depressed symptomology. For example, the HDRS score of the subject may be below 8 following treatment. [00432] In some embodiments, the measurement is an anxiety measurement. The anxiety measurement may include an assessment of a symptom of anxiety.
  • the symptom of anxiety includes stress, worry, or restlessness.
  • the symptom of anxiety includes one or more behavioral symptoms such as hypervigilance, irritability, or restlessness.
  • the symptom of anxiety includes one or more cognitive symptoms such as lack of concentration, racing thoughts, or unwanted thoughts.
  • the symptom of anxiety includes one or more whole body symptoms such as fatigue or sweating.
  • the symptoms of anxiety include any of excessive worry, fear, feeling of impending doom, insomnia, nausea, palpitations, or trembling.
  • the symptom includes one or more panic attacks.
  • the anxiety measurement may include a questionnaire or assessment.
  • the assessment may include an amount, frequency, duration, or intensity of the anxiety or symptoms of anxiety.
  • the anxiety measurement may include an amount of time since feeling anxious or since feeling symptoms of anxiety.
  • the anxiety measurement may include a frequency of feeling anxious or feeling symptoms of anxiety.
  • the composition reduces the anxiety measurement relative to the baseline anxiety measurement.
  • the composition may reduce the anxiety measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • Attorney Docket No.54462-754.601 [00433]
  • the measurement is an eating disorder measurement. Examples of eating disorders include anorexia, bulimia, binge eating disorder, pica, rumination, or avoidant eating disorder.
  • the eating disorder includes anorexia nervosa. In some embodiments, the eating disorder includes bulimia. In some embodiments, the eating disorder includes binge eating. In some embodiments, the eating disorder includes pica.
  • the eating disorder measurement may include an assessment of a symptom of eating disorder. Some examples of symptoms of an eating disorder comprising anorexia nervosa include being considerably underweight compared with people of similar age and height, very restricted eating patterns, an intense fear of gaining weight or persistent behaviors to avoid gaining weight despite being underweight, a relentless pursuit of thinness and unwillingness to maintain a healthy weight, a heavy influence of body weight or perceived body shape on self-esteem, a distorted body image, or denial of being seriously underweight.
  • the eating disorder measurement may include a questionnaire or assessment.
  • the assessment may include an amount, frequency, duration, or intensity of the eating disorder or symptoms.
  • the eating disorder measurement may include an amount of time since engaging in the eating disorder (e.g., binding, purging, or starving).
  • the eating disorder measurement may include a frequency of engaging in the eating disorder.
  • the composition reduces the eating disorder measurement relative to the baseline eating disorder measurement. For example, the composition may reduce the eating disorder measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00434]
  • the measurement is a substance-use measurement.
  • the substance-use measurement includes a determination of a level of addiction to an addictive substance.
  • addictive substances include alcohol, antianxiety drugs, sedative drugs, caffeine, cannabis (e.g., including marijuana or synthetic cannabinoids), hallucinogens (e.g., LSD, phencyclidine, or psilocybin), inhalants (e.g., paint thinner or some glues), opioids (e.g., fentanyl, morphine, or oxycodone), stimulants (e.g., amphetamines or cocaine), tobacco, or anabolic steroids.
  • the substance abuse measurement may include an amount of time since engaging in the substance-use disorder or experiencing symptoms of the substance-use disorder.
  • the substance abuse measurement may include a frequency of engaging in the substance-use disorder or experiencing symptoms of the substance-use disorder.
  • the determination of a level of addiction to an addictive substance may include a questionnaire or assessment.
  • the substance abuse measurement or the assessment may include an amount, frequency, duration, or intensity of the substance-use disorder or symptoms.
  • the determination of a level of addiction to an addictive substance may include an amount of time since ingesting the addictive substance.
  • the determination of a level of addiction to an addictive substance may include a frequency of ingesting the addictive substance.
  • the composition reduces the substance abuse measurement relative to the baseline substance abuse measurement.
  • the composition may reduce the e substance abuse measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • Attorney Docket No.54462-754.601 [00435]
  • the measurement is a PTSD measurement.
  • the PTSD measurement includes a determination of the level of severity of PTSD.
  • the assessment of a sign or symptom of PTSD may include the number of signs or symptoms of PTSD.
  • the determination of the level of severity of PTSD may include the time since last experiencing a PTSD flashback (e.g., reliving the traumatic event as if it were happening again), nightmare, or severe anxiety.
  • the assessment may include a frequency in PTSD related flashbacks, nightmares, or severe anxiety episodes.
  • the assessment may include a severity of a sign or symptom of PTSD.
  • the assessment may include a frequency of a sign or symptom of PTSD.
  • Exemplary signs and symptoms of PTSD may include intrusive memories (e.g., recurrent, unwanted distressing memories of a traumatic event, severe emotional distress or physical reactions to something that resemble of the traumatic event, attempts to avoid thinking or talking about the traumatic event, avoiding places, activities or people pronounced of the traumatic event, thoughts of hopelessness, memory problems, difficulty maintaining close relationships, and feeling a lack of interest in activities that were once enjoyed.
  • the composition reduces the PTSD measurement relative to the baseline substance abuse measurement.
  • the composition may reduce the PTSD measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a bipolar disorder measurement.
  • the bipolar disorder measurement is a sign or symptom of bipolar disorder.
  • the assessment of a sign or symptom of bipolar disorder may include a frequency of a sign or symptom of bipolar disorder.
  • the assessment of a sign or symptom of bipolar disorder may include a severity of a sign or symptom of bipolar disorder.
  • the assessment of a sign or symptom of bipolar disorder may include the number of signs or symptoms of bipolar disorder.
  • Exemplary signs and symptoms of bipolar disorder include any of the bipolar signs and symptoms disclosed herein, including, manic episodes (e.g., experiencing feelings of increased activity, energy, or agitation, an exaggerated sense of well-being and self-confidence, a decreased need for sleep, racing thoughts, distractibility, and a decreased ability to control impulses), and major depressive episodes (e.g., experiencing a depressed mood, marked loss of interest of feelings of pleasure, fatigue or loss of energy, feelings of guilt or worthlessness, and a decreased ability to think or concentrate).
  • the composition reduces the bipolar disorder measurement relative to the baseline substance abuse measurement.
  • the composition may reduce the bipolar disorder measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement comprises a schizophrenia measurement.
  • the schizophrenia measurement is a sign or symptom of schizophrenia.
  • the assessment of a sign or symptom of schizophrenia may include a frequency of a sign or symptom of schizophrenia.
  • the assessment of a sign or symptom of schizophrenia may include a severity of a sign or symptom of schizophrenia.
  • the assessment of a sign or symptom of schizophrenia may include the number of signs or symptoms of schizophrenia.
  • Exemplary signs and symptoms of schizophrenia may include delusions, Attorney Docket No.54462-754.601 hallucinations, disorganized thoughts and speech, disorganized or abnormal motor behavior, and negative symptoms (e.g., social withdrawal, anhedonia, avolition, decreased sense of purpose, lack of interest in activities, flat affect, lack of eye contact, and physical inactivity.
  • the composition reduces the schizophrenia measurement relative to the baseline substance abuse measurement.
  • the composition may reduce the schizophrenia measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement comprises a psychosis measurement.
  • the psychosis measurement is a sign or symptom of psychosis.
  • the assessment of a sign or symptom of psychosis may include a frequency of a sign or symptom of psychosis.
  • the assessment of a sign or symptom of psychosis may include a severity of a sign or symptom of psychosis.
  • the assessment of a sign or symptom of psychosis may include the number of signs or symptoms of psychosis.
  • Exemplary signs and symptoms of psychosis may include difficulty concentrating, depressed mood, anxiety, excessive suspiciousness, delusions, and hallucinations.
  • the composition reduces the schizophrenia measurement relative to the baseline psychosis measurement.
  • the composition may reduce the psychosis measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement comprises a measurement of a neurological disorder.
  • Non-limiting examples of measurements of neurological disorders include a cognitive function measurement, an amyloid plaque measurement, a tau accumulation measurement, a beta-amyloid 42 measurement, a beta-amyloid 40 measurement, the ratio of beta-amyloid 42 to beta-amyloid 40 measurement, a tau measurement, a phospho-tau measurement (such a p-tau217), a neurofilament light chain (NfL) measurement, a glial fibrillary acidic protein (GFAP) measurement, an alpha-synuclein measurement, a Lewy body measurement.
  • a cognitive function measurement an amyloid plaque measurement, a tau accumulation measurement, a beta-amyloid 42 measurement, a beta-amyloid 40 measurement, the ratio of beta-amyloid 42 to beta-amyloid 40 measurement, a tau measurement, a phospho-tau measurement (such a p-tau217), a neurofilament light chain (NfL) measurement, a glial fibrillary acidic protein (
  • measurements include a measurement of headache signs and/or symptoms, a measurement of migraine symptoms and/or signs, a measurement of chronic pain symptoms and/or signs, a measurement of fibromyalgia symptoms and/or signs, a measurement of chronic fatigue syndrome (ME) symptoms and/or signs, a measurement of chronic traumatic encephalopathy symptoms and/or signs, a measurement of traumatic brain injury symptoms and/or signs, and a measurement of motor neuron disease (e.g., ALS) symptoms and/or signs.
  • the composition improves the neurological disorder measurement relative to the baseline neurological disorder measurement.
  • the composition may improve the neurological disorder measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a cognitive function measurement.
  • the cognitive function measurement may be obtained directly from the subject.
  • the subject may be administered a test.
  • the test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or Mini-Cog.
  • the test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial Attorney Docket No.54462-754.601 ability, behavior, mood, orientation, or attention.
  • the cognitive function measurement may include a score.
  • the cognitive function measurement may be indicative of a lack of cognitive impairment.
  • the cognitive function measurement is indicative of mild cognitive impairment
  • the baseline cognitive function measurement is indicative of severe cognitive impairment.
  • the cognitive function measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease, dementia, or cognitive impairment.
  • the composition increases the cognitive function measurement relative to the baseline cognitive function measurement.
  • the increase is measured directly in the subject after administering the composition to the subject.
  • the cognitive function measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline cognitive function measurement.
  • the cognitive function measurement is increased by about 10% or more, relative to the baseline cognitive function measurement.
  • the cognitive function measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline cognitive function measurement.
  • the cognitive function measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 10%, relative to the baseline cognitive function measurement.
  • the cognitive function measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline cognitive function measurement.
  • the cognitive function measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is an amyloid plaque measurement.
  • the amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement.
  • the amyloid plaque measurement includes a concentration or amount.
  • the amyloid plaque measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • PET positron emission tomography
  • the amyloid plaque measurement may be performed using a spinal tap (for example, when the amyloid plaque measurement includes a cerebrospinal fluid (CSF) amyloid plaque measurement).
  • the amyloid plaque measurement is obtained by an assay such as an immunoassay.
  • the beta amyloid plaque measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease.
  • the composition reduces the amyloid plaque measurement relative to the baseline amyloid plaque measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured directly in the subject after administering the composition to the subject.
  • the amyloid plaque measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline amyloid plaque measurement.
  • the amyloid plaque measurement is decreased by about 10% or more, relative to the baseline amyloid plaque measurement.
  • the amyloid plaque measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline amyloid plaque measurement.
  • the amyloid plaque measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 10%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline amyloid plaque measurement.
  • the amyloid plaque measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a beta-amyloid 42 measurement.
  • the beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) or plasma beta-amyloid 42 measurement.
  • the beta-amyloid 42 measurement includes a concentration or amount.
  • the beta-amyloid 42 measurement may be performed on a biopsy.
  • the beta-amyloid 42 measurement may be performed on a blood sample.
  • the beta-amyloid 42 measurement may be performed using a spinal tap (for example, when the beta-amyloid 42 measurement includes a CSF beta-amyloid 42 measurement).
  • the beta-amyloid 42 measurement is obtained by an assay such as an immunoassay.
  • the beta-amyloid 42 measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease.
  • the composition improves the CSF or plasma beta-amyloid 42 measurement relative to the baseline beta-amyloid 42 measurement.
  • the reduction is measured in a second sample (for example, a CSF or blood plasma sample) obtained from the subject after administering the composition to the subject.
  • the CSF or plasma beta-amyloid 42 measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF or plasma beta-amyloid 42 measurement.
  • the CSF or plasma Attorney Docket No.54462-754.601 beta-amyloid 42 measurement is improved by about 10% or more, relative to the baseline CSF or plasma beta-amyloid 42 measurement.
  • the CSF or plasma beta-amyloid 42 measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF or plasma beta-amyloid 42 measurement.
  • the CSF or plasma beta-amyloid 42 measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF or plasma beta-amyloid 42 measurement. In some embodiments, the CSF or plasma beta-amyloid 42 measurement is improved by no more than about 10%, relative to the baseline CSF or plasma beta-amyloid 42 measurement. In some embodiments, the CSF or plasma beta- amyloid 42 measurement is improved by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF or plasma beta-amyloid 42 measurement.
  • the beta-amyloid 42 measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline beta-amyloid 42 measurement.
  • the CSF or plasma beta-amyloid 42 measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a beta-amyloid 40 measurement.
  • the beta-amyloid 40 measurement may include a cerebrospinal fluid (CSF) or plasma beta-amyloid 40 measurement.
  • CSF cerebrospinal fluid
  • the beta-amyloid 40 measurement includes a concentration or amount.
  • the beta-amyloid 40 measurement may be performed on a biopsy.
  • the beta-amyloid 40 measurement may be performed on a blood sample.
  • the beta-amyloid 40 measurement may be performed using a spinal tap (for example, when the beta-amyloid 40 measurement includes a CSF beta-amyloid 40 measurement).
  • the beta-amyloid 40 measurement is obtained by an assay such as an immunoassay.
  • the beta-amyloid 40 measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease.
  • the composition improves the CSF or plasma beta-amyloid 40 measurement relative to the baseline beta-amyloid 40 measurement.
  • the reduction is measured in a second sample (for example, a CSF or blood plasma sample) obtained from the subject after administering the composition to the subject.
  • the CSF or plasma beta-amyloid 40 measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF or plasma beta-amyloid 40 measurement.
  • the CSF or plasma beta-amyloid 40 measurement is improved by about 10% or more, relative to the baseline CSF or plasma beta-amyloid 40 measurement. In some embodiments, the CSF or plasma beta-amyloid 40 measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF or plasma beta-amyloid 40 measurement. In some embodiments, the CSF or plasma beta-amyloid 40 Attorney Docket No.54462-754.601 measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF or plasma beta-amyloid 40 measurement.
  • the CSF or plasma beta-amyloid 40 measurement is improved by no more than about 10%, relative to the baseline CSF or plasma beta-amyloid 40 measurement. In some embodiments, the beta-amyloid 40 measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline beta-amyloid 40 measurement.
  • the CSF or plasma beta-amyloid 40 measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement may include a cerebrospinal fluid (CSF) or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement includes a concentration or amount.
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement may be performed on a biopsy.
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement may be performed on a blood sample.
  • the ratio of beta- amyloid 42 to beta-amyloid 40 measurement may be performed using a spinal tap (for example, when the ratio of beta-amyloid 42 to beta-amyloid 40 measurement includes a CSF ratio of beta-amyloid 42 to beta- amyloid 40 measurement).
  • the ratio of beta-amyloid 42 to beta-amyloid 40 measurement is obtained by an assay such as an immunoassay.
  • the ratio of beta-amyloid 42 to beta- amyloid 40 measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease.
  • the composition improves the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement relative to the baseline ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the reduction is measured in a second sample (for example, a CSF or blood plasma sample) obtained from the subject after administering the composition to the subject.
  • the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement is improved by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement is improved by about 10% or more, relative to the baseline CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement is improved by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement. In some embodiments, the CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement is improved by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the CSF or plasma ratio of beta-amyloid 42 to beta- Attorney Docket No.54462-754.601 amyloid 40 measurement is improved by no more than about 10%, relative to the baseline CSF or plasma ratio of beta-amyloid 42 to beta-amyloid 40 measurement.
  • the ratio of beta- amyloid 42 to beta-amyloid 40 measurement is improved by no more than about 100%, improved by no more than about 250%, improved by no more than about 500%, improved by no more than about 750%, or improved by no more than about 1000%, relative to the baseline ratio of beta-amyloid 42 to beta- amyloid 40 measurement.
  • the CSF or plasma ratio of beta-amyloid 42 to beta- amyloid 40 measurement is improved by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a tau measurement.
  • the tau measurement includes a concentration or amount.
  • the tau measurement may include a central nervous system (CNS) tau measurement.
  • the tau measurement includes a concentration or amount.
  • the tau measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • the tau measurement may be performed on a biopsy.
  • the tau measurement is obtained by an assay such as an immunoassay.
  • the beta tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the tau measurement is a central nervous system (CNS) tau measurement.
  • the tau measurement may include a total tau measurement.
  • the tau measurement may include a unphosphorylated tau measurement.
  • the tau measurement may include a phosphorylated tau measurement.
  • the tau measurement is a tau accumulation measurement.
  • the tau measurement is a CNS tau accumulation measurement.
  • the CNS tau accumulation measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the composition reduces the CNS tau accumulation measurement relative to the baseline CNS tau accumulation measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the CNS tau accumulation measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by about 10% or more, relative to the baseline CNS tau accumulation measurement.
  • the CNS tau accumulation measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 10%, relative to the baseline CNS tau accumulation measurement.
  • the CNS tau accumulation measurement is decreased Attorney Docket No.54462-754.601 by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CNS tau accumulation measurement.
  • the CNS tau accumulation measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the tau measurement may include a cerebrospinal fluid (CSF) tau measurement or a plasma tau measurement.
  • CSF cerebrospinal fluid
  • the plasma tau measurement may be performed after use of a blood sample.
  • the CSF tau measurement may be performed after use of a spinal tap.
  • the CSF tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the composition reduces the CSF or plasma tau measurement relative to the baseline CSF or plasma tau measurement.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured in a second CSF or plasma sample obtained from the subject after administering the composition to the subject.
  • the CSF or plasma tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF or plasma tau measurement. In some embodiments, the CSF or plasma tau measurement is decreased by about 10% or more, relative to the baseline CSF or plasma tau measurement. In some embodiments, the CSF or plasma tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF or plasma tau measurement. In some embodiments, the CSF or plasma tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF or plasma tau measurement.
  • the CSF or plasma tau measurement is decreased by no more than about 10%, relative to the baseline CSF or plasma tau measurement. In some embodiments, the CSF or plasma tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF or plasma tau measurement. In some embodiments, the CSF or plasma tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the tau measurement may include a CSF or plasma phospho-tau measurement (such as p- tau217).
  • the CSF or plasma phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau.
  • the CSF or plasma phospho-tau measurement may include a phospho-tau/tau ratio.
  • the CSF or plasma phospho-tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.
  • the composition reduces the CSF or plasma phospho-tau measurement relative to the baseline CSF or plasma phospho-tau measurement.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured in a second CSF or plasma sample obtained from the subject after administering the composition to the subject.
  • the CSF or plasma phospho-tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF or plasma phospho-tau measurement.
  • the CSF or plasma phospho-tau measurement is decreased by about 10% or more, relative to the baseline CSF or plasma phospho-tau measurement. In some embodiments, the CSF or plasma phospho-tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF or plasma phospho-tau measurement. In some embodiments, the CSF or plasma phospho-tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF or plasma phospho-tau measurement.
  • the CSF or plasma phospho-tau measurement is decreased by no more than about 10%, relative to the baseline CSF or plasma phospho-tau measurement. In some embodiments, the CSF or plasma phospho-tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF or plasma phospho-tau measurement.
  • the CSF or plasma phospho-tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a neurofilament light chain (NfL) measurement.
  • the NfL measurement includes a CSF or plasma NfL measurement.
  • the NfL measurement may be a CSF NfL measurement.
  • the NfL measurement may be a plasma NfL measurement.
  • the NfL measurement may include a concentration or an amount.
  • the NfL measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease, ALS or Parkinson’s disease.
  • the composition reduces the NfL measurement relative to the baseline NfL measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the NfL measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by about 10% or more, relative to the baseline NfL measurement.
  • the NfL measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline NfL measurement. In some embodiments, the NfL Attorney Docket No.54462-754.601 measurement is decreased by no more than about 10%, relative to the baseline NfL measurement.
  • the NfL measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00459] In some embodiments, the measurement is a glial fibrillary acidic protein (GFAP) measurement. In some embodiments, the GFAP measurement includes a CSF or plasma GFAP measurement.
  • GFAP glial fibrillary acidic protein
  • the GFAP measurement may be a CSF GFAP measurement.
  • the GFAP measurement may be a plasma GFAP measurement.
  • the GFAP measurement may include a concentration or an amount.
  • the GFAP measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer’s disease, dementia, or cognitive impairment.
  • the composition reduces the GFAP measurement relative to the baseline GFAP measurement.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the GFAP measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline GFAP measurement.
  • the GFAP measurement is decreased by about 10% or more, relative to the baseline GFAP measurement. In some embodiments, the GFAP measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline GFAP measurement. In some embodiments, the GFAP measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline GFAP measurement. In some embodiments, the GFAP measurement is decreased by no more than about 10%, relative to the baseline GFAP measurement.
  • the GFAP measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline GFAP measurement. In some embodiments, the GFAP measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. In some instances, the fibrinogen measurement comprises a measurement of fibrinogen in blood. In some instances, the fibrinogen measurement comprises a measurement of fibrinogen in plasma.
  • the measurement is a alpha-synuclein measurement.
  • the alpha-synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement.
  • CSF cerebrospinal fluid
  • the alpha-synuclein measurement includes a concentration or amount.
  • the alpha-synuclein measurement may be performed on a biopsy.
  • the alpha-synuclein measurement may be performed using a spinal tap (for example, when the alpha-synuclein measurement includes a CSF alpha-synuclein measurement).
  • the alpha-synuclein measurement is obtained by an assay such as Attorney Docket No.54462-754.601 an immunoassay.
  • the alpha-synuclein measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Parkinson’s disease.
  • the alpha-synuclein measurement may be indicative of a treatment effect of the oligonucleotide on dementia.
  • the composition reduces the alpha-synuclein measurement relative to the baseline alpha-synuclein measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the alpha-synuclein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 10% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline alpha-synuclein measurement.
  • the alpha-synuclein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 10%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline alpha-synuclein measurement.
  • the alpha-synuclein measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a Lewy body measurement.
  • the Lewy body measurement may include a central nervous system (CNS) Lewy body measurement.
  • the Lewy body measurement includes a concentration or amount.
  • the Lewy body measurement may be performed using an imaging device.
  • the imaging device may include a positron emission tomography (PET) device.
  • PET positron emission tomography
  • the beta Lewy body measurement may be indicative of a treatment effect of the oligonucleotide on dementia.
  • the composition reduces the Lewy body measurement relative to the baseline Lewy body measurement.
  • the reduction is measured in a second sample obtained from the subject after administering the composition to the subject.
  • the reduction is measured directly in the subject after administering the composition to the subject.
  • the Lewy body measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline Lewy body measurement.
  • the Lewy body measurement is decreased by about 10% or more, relative to the baseline Lewy body measurement.
  • the Lewy body measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline Lewy body measurement.
  • the Attorney Docket No.54462-754.601 Lewy body measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline Lewy body measurement.
  • the Lewy body measurement is decreased by no more than about 10%, relative to the baseline Lewy body measurement.
  • the Lewy body measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00465] In some embodiments, the measurement is a headache measurement. Some embodiments, the headache measurement is a headache sign or symptom measurement.
  • the headache measurement is a migraine (e.g., with aura or without aura) measurement.
  • the headache measurement is a frequency of a headache sign or symptom measurement.
  • the headache measurement is a severity of a headache sign or symptom measurement.
  • the headache measurement is a number of headache signs or symptoms. Exemplary signs and symptoms of headaches include pain (e.g., deep and constant) in the cheekbones, forehead, bridge of the nose, the cranium, or the back of the neck, aura, photophobia, phonophobia, and emesis.
  • the composition reduces the headache measurement relative to the baseline headache measurement.
  • the composition may reduce the headache measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a chronic pain measurement.
  • chronic pain measurement is a fibromyalgia measurement.
  • the chronic pain measurement is a chronic pain sign or symptom measurement.
  • the chronic pain measurement is a frequency of a chronic pain sign or symptom measurement.
  • the chronic pain measurement is a severity of a chronic pain sign or symptom measurement.
  • the chronic pain measurement is a number of chronic pain signs or symptoms.
  • Exemplary signs and symptoms of fibromyalgia include muscular pain, fatigues, depression, anxiety, sleeplessness, headache, and difficulty concentrating.
  • Exemplary chronic pain disorders include postsurgical pain, post- trauma pain, low back pain, cancer pain, arthritis pain, muscular pain, and neuropathic pain (e.g., diabetic neuropathy).
  • the composition reduces the chronic pain (e.g., fibromyalgia) measurement relative to the baseline chronic pain (e.g., fibromyalgia) measurement.
  • the composition may reduce the chronic pain (e.g., fibromyalgia) measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a chronic fatigue syndrome (also referred to as myalgic encephalomyelitis) measurement.
  • the chronic fatigue syndrome measurement is a chronic fatigue syndrome sign or symptom measurement.
  • the Attorney Docket No.54462-754.601 chronic fatigue syndrome measurement is a frequency of a headache sign or symptom measurement.
  • the chronic fatigue syndrome measurement is a severity of a chronic fatigue syndrome sign or symptom measurement.
  • the chronic fatigue syndrome measurement is a number of chronic fatigue syndrome signs or symptoms. Exemplary signs and symptoms of chronic fatigue syndrome include extreme fatigue that lasts for extended periods of time (e.g., for at least six months) that cannot be fully explained by an underlying medical condition, fatigue that worsens with physical or mental activity, pain (e.g., joint or muscular), malaise, forgetfulness, anxiety, and depression.
  • the composition reduces the chronic fatigue syndrome measurement relative to the baseline chronic fatigue syndrome measurement.
  • the composition may reduce the chronic fatigue syndrome measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a chronic traumatic encephalopathy measurement.
  • the chronic traumatic encephalopathy measurement is a chronic traumatic encephalopathy sign or symptom measurement.
  • the chronic traumatic encephalopathy measurement is a number of chronic traumatic encephalopathy signs or symptoms measurement.
  • Exemplary signs and symptoms of chronic traumatic encephalopathy include cognitive impairment, dementia, agitation, disorientation, playful or unusual behavior, depression, suicidal behavior or threats of self-injury, and movement disorders.
  • the composition reduces the chronic traumatic encephalopathy measurement relative to the baseline chronic traumatic encephalopathy measurement.
  • the composition may reduce the chronic traumatic encephalopathy measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a traumatic brain injury measurement.
  • the traumatic brain injury measurement is a traumatic brain injury sign or symptom measurement. In some embodiments, the traumatic brain injury measurement is a number of traumatic brain injury signs or symptoms measurement. Exemplary signs and symptoms of traumatic brain injury include cognitive deficits, motor deficits, sensory or perceptual deficits, communication or language deficits, functional deficits, social difficulties, regulatory disturbances, personality changes and mood disorders, and traumatic epilepsy. In some embodiments, the composition reduces the traumatic brain injury measurement relative to the baseline traumatic brain injury measurement.
  • the composition may reduce the traumatic brain injury measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a motor neuron disease measurement.
  • the motor neuron disease measurement is an amyotrophic lateral sclerosis (ALS) measurement.
  • the motor neuron disease measurement is a motor neuron disease sign or symptom measurement.
  • the motor neuron disease measurement is a Attorney Docket No.54462-754.601 frequency of a motor neuron disease sign or symptom measurement.
  • the motor neuron disease measurement is a severity of a motor neuron disease sign or symptom measurement. In some embodiments, the motor neuron disease measurement is a number of motor neuron disease signs or symptoms. Exemplary forms of motor neuron diseases include progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), ALS, and primary lateral sclerosis (PLS). Exemplary signs and symptoms of motor neuron diseases include motor control difficulties (e.g., difficulty walking or completing normal daily activities), muscular weakness, slurred speech, difficulty swallowing, and muscle cramps and twitching (e.g., in the arms, shoulders, or tongue).
  • PBP progressive bulbar palsy
  • PMA progressive muscular atrophy
  • ALS ALS
  • PLS primary lateral sclerosis
  • Exemplary signs and symptoms of motor neuron diseases include motor control difficulties (e.g., difficulty walking or completing normal daily activities), muscular weakness, slurred speech, difficulty swallowing, and muscle cramps and twitching (e.g., in the arms, shoulders
  • the composition reduces the motor neuron disease (e.g., ALS) measurement relative to the baseline chronic fatigue syndrome measurement.
  • the composition may reduce the motor neuron disease (e.g., ALS) measurement by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.
  • the measurement is a fibrinogen measurement.
  • the measurement may comprise a fibrin measurement. Where a fibrinogen level or measurement is described, a fibrin level or measurement may also be contemplated, since fibrin may be considered a degradation product of fibrinogen.
  • the measurement is a measurement of circulating fibrinogen.
  • the composition reduces the fibrinogen measurement relative to the baseline fibrinogen measurement. In some embodiments, the composition reduces the circulating fibrinogen measurement relative to the baseline circulating fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by about 10% or more, relative to the baseline fibrinogen measurement.
  • the fibrinogen measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by no more than about 10%, relative to the baseline fibrinogen measurement.
  • the fibrinogen measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline fibrinogen measurement. In some embodiments, the fibrinogen measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. In some instances, the fibrinogen measurement comprises a measurement of fibrinogen in blood. In some instances, the fibrinogen measurement comprises a measurement of fibrinogen in plasma.
  • measurement is a central nervous system (CNS) fibrinogen measurement.
  • the measurement may include a CNS fibrin measurement.
  • the CNS fibrinogen measurement may include Attorney Docket No.54462-754.601 a brain fibrinogen measurement.
  • a CNS fibrinogen measurement may also be contemplated.
  • a CSF fibrinogen measurement may also be contemplated.
  • a FGG protein measurement may also be contemplated.
  • a CNS, brain, or CSF fibrinogen measurement may include a CNS, brain, or CSF FGG protein measurement.
  • measurement is a brain fibrinogen measurement.
  • the composition reduces the brain fibrinogen measurement relative to a baseline brain fibrinogen measurement.
  • the brain fibrinogen measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline brain fibrinogen measurement.
  • the brain fibrinogen measurement is decreased by about 10% or more, relative to the baseline brain fibrinogen measurement.
  • the brain fibrinogen measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline brain fibrinogen measurement.
  • the brain fibrinogen measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline brain fibrinogen measurement. In some embodiments, the brain fibrinogen measurement is decreased by no more than about 10%, relative to the baseline brain fibrinogen measurement. In some embodiments, the brain fibrinogen measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline brain fibrinogen measurement.
  • the brain fibrinogen measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages [00473]
  • the measurement is a clotting or coagulation measurement.
  • the clotting or coagulation measurement is a prothrombin time (PT).
  • the clotting or coagulation measurement is an International Normalized Ratio (INR).
  • the clotting or coagulation measurement is an activated partial thromboplastin time (aPTT).
  • the composition reduces the clotting or coagulation measurement relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is increased by about 10% or more, relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is Attorney Docket No.54462-754.601 increased by no more than about 10%, relative to the baseline clotting or coagulation measurement.
  • the clotting or coagulation measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline clotting or coagulation measurement.

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Abstract

La présente invention concerne des compositions contenant un oligonucléotide ciblant le FGG. L'oligonucléotide peut comprendre un petit ARN interférent (ARNsi) ou un oligonucléotide antisens (ASO). La présente invention porte également sur des méthodes de traitement d'un trouble mental ou d'une affection associée à une mutation de FGG. La méthode peut consister à fournir à un sujet un oligonucléotide ciblant le FGG.
PCT/US2024/032448 2023-06-05 2024-06-04 Traitement de maladies et de troubles liés au fgg Pending WO2024254091A1 (fr)

Applications Claiming Priority (6)

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US202363471231P 2023-06-05 2023-06-05
US63/471,231 2023-06-05
US202363582786P 2023-09-14 2023-09-14
US63/582,786 2023-09-14
US202363585551P 2023-09-26 2023-09-26
US63/585,551 2023-09-26

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114369657A (zh) * 2022-01-25 2022-04-19 基诺莱(重庆)生物技术有限公司 一种易栓症基因突变的多重pcr检测方法和试剂盒
WO2022133344A1 (fr) * 2020-12-18 2022-06-23 Genevant Sciences Gmbh Lipides peg et nanoparticules lipidiques
US20220364096A1 (en) * 2020-03-06 2022-11-17 Aligos Therapeutics, Inc. Modified Short Interfering Nucleic Acid (siNA) Molecules and Uses Thereof
WO2023107896A1 (fr) * 2021-12-06 2023-06-15 Empirico Inc. Traitement de maladies et de troubles liés au fgg

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220364096A1 (en) * 2020-03-06 2022-11-17 Aligos Therapeutics, Inc. Modified Short Interfering Nucleic Acid (siNA) Molecules and Uses Thereof
WO2022133344A1 (fr) * 2020-12-18 2022-06-23 Genevant Sciences Gmbh Lipides peg et nanoparticules lipidiques
WO2023107896A1 (fr) * 2021-12-06 2023-06-15 Empirico Inc. Traitement de maladies et de troubles liés au fgg
CN114369657A (zh) * 2022-01-25 2022-04-19 基诺莱(重庆)生物技术有限公司 一种易栓症基因突变的多重pcr检测方法和试剂盒

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