WO2026006477A1 - Compositions oligonucléotidiques et méthodes associées - Google Patents

Compositions oligonucléotidiques et méthodes associées

Info

Publication number
WO2026006477A1
WO2026006477A1 PCT/US2025/035290 US2025035290W WO2026006477A1 WO 2026006477 A1 WO2026006477 A1 WO 2026006477A1 US 2025035290 W US2025035290 W US 2025035290W WO 2026006477 A1 WO2026006477 A1 WO 2026006477A1
Authority
WO
WIPO (PCT)
Prior art keywords
wve
subject
htt
administered
linkage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/035290
Other languages
English (en)
Other versions
WO2026006477A8 (fr
Inventor
Stephen Lister LAKE
Xiao Shelley HU
Jianxin Gao
Yilin Zhang
Philip Ross
Vincent ADUDA
Mamoru Shimizu
Danlin Xu
Keith Andrew BOWMAN
Sarah Diane LAMORE
Michael Angelo PANZARA
Mohammed Rowshon ALAM
Hyun Gyung Jang
Asela Kalyanapriya BANDARA
Joseph Andrew HAEGELE
Mark Richard Hurtt
Varun Goel
Padmakumar NARAYANAN
Anne-Marie Li-Kwai-Cheung
Cynthia Fajardo CARACTA
Anthony TROMBINO
Lanyi XIE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wave Life Sciences Pte Ltd
Original Assignee
Wave Life Sciences Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2024/040849 external-priority patent/WO2025030155A1/fr
Application filed by Wave Life Sciences Pte Ltd filed Critical Wave Life Sciences Pte Ltd
Publication of WO2026006477A1 publication Critical patent/WO2026006477A1/fr
Publication of WO2026006477A8 publication Critical patent/WO2026006477A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • 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
    • 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
    • C12N2310/11—Antisense
    • 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
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/34—Allele or polymorphism specific uses
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/35—Special therapeutic applications based on a specific dosage / administration regimen

Definitions

  • provided herein are methods of administering WVE-003 for ameliorating Huntington’s disease, reducing mHTT RNA, or reducing mHTT protein in a human subject in need thereof.
  • methods are useful for ameliorating at least one symptom of Huntington’s disease.
  • symptoms of Huntington’s disease include, but are not limited to, brain atrophy, muscle atrophy, nerve degeneration, uncontrolled movement, difficulty swallowing, difficulty speaking, anxiety and depression.
  • BACKGROUND [0003] Oligonucleotides are useful in therapeutic, diagnostic, research and nanomaterials applications.
  • the present disclosure provides technologies for preventing or treating Huntington’s disease, comprising administering or delivering to a subject susceptible thereto or suffering therefrom WVE-003 equivalent to about 30 mg WVE-003 free acid form about every 8 weeks or less frequently (e.g., about every 8 weeks, about every 12 weeks, about quarterly, etc.).
  • the present disclosure provides technologies for preventing or treating Huntington’s disease, comprising administering or delivering to a subject susceptible thereto or suffering therefrom multiple doses (e.g., three or more) of WVE-003, each of which is independently equivalent to about 30 mg WVE-003 free acid form, about every 8 weeks or less frequently (e.g., about every 8 weeks, about every 12 weeks, quarterly, etc.).
  • multiple doses e.g., three or more
  • WVE-003 e.g., three or more
  • WVE-003 e.g., three or more
  • the present disclosure provides the first-ever clinical demonstration of allele- 1 of 265 12842751v1 Attorney Docket No.: 2010581-1510 selective silencing of any disease target.
  • the present disclosure demonstrates mutant huntingtin (mHTT) protein lowering of 46% with preservation of wild-type huntingtin (wtHTT) protein.
  • mHTT mutant huntingtin
  • wtHTT wild-type huntingtin
  • statistically significant, potent, and durable allele-selective silencing was demonstrated in a 30 mg multidose WVE-003 cohort: 46% mean reduction in CSF mHTT protein compared to placebo, preservation of wtHTT protein, and generally safe and well-tolerated profile were achieved in a 30 mg multidose WVE-003 cohort.
  • the present disclosure demonstrates that reductions in mHTT significantly correlates with a slowing in caudate atrophy (e.g., after just 28 weeks), an imaging biomarker predictive of clinical outcomes.
  • WVE-003 which may also be referred to as WV-21405, has the structure of: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents a Rp n001 linkage, wherein a n001 linkage has the structure ; eo represents a 2’ ⁇ OCH2CH2OCH3
  • a nucleoside is a DNA nucleoside and a linkage is a natural phosphate linkage.
  • WVE-003 can be provided in various forms including pharmaceutically acceptable salt forms such as sodium salt.
  • HTT Hetin
  • base sequence e.g., base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages, and patterns thereof), and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages), and/or patterns thereof]
  • stereochemistry e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages), and/or patterns thereof
  • HTT oligonucleotide properties and/or activities e.g., protein binding characteristics, stability, toxicities, delivery, allele-specific knockdown of HTT transcripts, etc.
  • the present disclosure demonstrates that HTT oligonucleotides with controlled structural elements and compositions thereof can provide unexpected therapeutic properties and activities.
  • the present disclosure provides technologies, e.g., HTT oligonucleotides, pharmaceutical compositions, drug 2 of 265 12842751v1 Attorney Docket No.: 2010581-1510 products, doses, dosages, etc., particularly those of WVE-003, that are useful for treating Huntington’s disease in a subject.
  • a subject has a HTT allele or transcript that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE-003.
  • a nucleic acid or base sequence may be considered as fully complementary to another nucleic acid (e.g., WVE-003) or base sequence if the nucleic acid or base sequence comprises a sequence that has the same length as the another nucleic acid or base sequence and is fully complementary to the full base sequence of the another nucleic acid (e.g., WVE-003) or base sequence.
  • an expanded CAG repeat comprises 36 or more CAG repeats.
  • a subject comprises a HTT transcript associated with Huntington’s disease, wherein the transcript is fully complementary to the base sequence of WVE-003.
  • a subject comprises a HTT transcript associated with Huntington’s disease, wherein the transcript is fully complementary to the base sequence of WVE-003 at SNP rs362273. In some embodiments, a subject comprises a HTT transcript that is fully complementary to the base sequence of WVE-003 and comprises an expanded CAG repeat region. In some embodiments, a subject comprises a HTT transcript that is fully complementary to the base sequence of WVE-003 at SNP rs362273 and comprises an expanded CAG repeat region.
  • a subject comprises a HTT nucleic acid, e.g., a HTT gene, which encodes a HTT transcript associated with Huntington’s disease, wherein the transcript is fully complementary to the base sequence of WVE-003.
  • a subject comprises a HTT nucleic acid, e.g., a HTT gene, which encodes a HTT transcript associated with Huntington’s disease, wherein the transcript is fully complementary to the base sequence of WVE-003 at SNP rs362273.
  • a subject comprises a HTT nucleic acid, e.g., a HTT gene, which encodes a HTT transcript that is fully complementary to the base sequence of WVE-003 and comprises an expanded CAG repeat region.
  • a subject comprises a HTT nucleic acid, e.g., a HTT gene, which encodes a HTT transcript that is fully complementary to the base sequence of WVE-003 at SNP rs362273 and comprises an expanded CAG repeat region.
  • a subject has an A variant of SNP rs362273.
  • HTT transcripts with an A variant of SNP rs362273 can be fully complementary to the base sequence of WVE-003, wherein the A is complementary to a T in WVE-003.
  • the A variant of SNP rs362273 is on the same chromosome as an expanded CAG repeat region in HTT.
  • a subject has a variant of SNP rs362273 that is not A.
  • a variant of SNP rs362273 that is not A is not on the same chromosome as an expanded CAG repeat region in HTT.
  • a variant of SNP rs362273 is C.
  • both chromosomes of a subject independently have an expanded CAG repeat region in HTT. 3 of 265 12842751v1 Attorney Docket No.: 2010581-1510 [0010]
  • Huntington’s disease is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline, psychiatric illness and chorea.
  • HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions and movement.
  • HD is reported to be caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT protein.
  • CAG cytosine-adenine-guanine
  • HTT mutant HTT causes progressive loss of neurons in the brain.
  • wild-type, or healthy, HTT protein is critical for neuronal function, and suppression may have detrimental long-term consequences.
  • approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for inheriting the disease. There are currently no approved disease- modifying therapies available.
  • Huntington’s disease is reportedly caused by a cytosine-adenine- guanine (CAG) repeat expansion in the Huntingtin (HTT) gene, resulting in mutant HTT (mHTT) protein production.
  • CAG cytosine-adenine- guanine
  • wtHTT wild-type HTT
  • wtHTT protein is reportedly critical for neuronal function; suppression of wtHTT may have detrimental long-term consequences.
  • the ability to selectively lower production of mHTT protein while retaining a sufficient wtHTT level reportedly holds great promise for HD treatment.
  • oligonucleotide administrations as described herein can reduce level, expression and/or activity of mHTT transcripts and/or proteins more than those of wtHTT transcripts and/or proteins in individual subjects and/or populations of subjects.
  • allele-specific knockdown utilizes an association between single nucleotide polymorphisms (SNPs) and genetic mutations to specifically target errors in genetic disorders, including Huntington’s disease (HD).
  • SNPs single nucleotide polymorphisms
  • HD Huntington’s disease
  • the present disclosure provides oligonucleotides, compositions and methods for allele-specific knockdown of a mHTT transcript, wherein allele-specific knockdown (also referenced as allele-specific suppression, allele-selective approach, allele-selective knockdown or suppression, or the like) preferentially decreases the level, expression and/or activity of a mHTT transcript (e.g., comprising an expanded CAG repeat region) and/or a product thereof (e.g., mHTT protein) relative to a wild-type HTT and/or a product thereof (e.g., wild-type HTT protein) (e.g., the expression, level and/or activity of wild-type HTT is not significantly decreased, not decreased, remains the same, or increases).
  • allele-specific knockdown also referenced as allele-specific suppression, allele-selective approach, allele-selective knockdown or suppression, or the like
  • allele-specific knockdown also referenced as allele-specific
  • a decrease in the level, expression and/or activity of a mHTT transcript results in or is associated with a decrease in the level, expression and/or activity of a mHTT protein, including but not limited to the formation, number and/or size of aggregates (coagula) of mHTT proteins.
  • a mHTT protein comprises an extended poly-glutamine (poly-Q) tract, e.g., translated from a CAG repeat expansion.
  • the present disclosure pertains to: a method of treatment and/or prevention of Huntington’s disease in a subject (e.g., a patient such as a human patient) in need thereof; a method of allele- specific knockdown of a mutant Huntingtin transcript in a subject; and/or a method for reducing the severity of and/or delaying the onset of one or more symptoms of Huntington’s disease.
  • the method comprises the step of administering to the subject a therapeutically effective amount of a HTT oligonucleotide or HTT oligonucleotide composition.
  • the present disclosure pertains to: a method of treating, ameliorating, or slowing the onset or progression of Huntington's Disease, comprising administering to a subject a compound comprising a HTT oligonucleotide or HTT oligonucleotide composition, wherein the oligonucleotide is complementary to a mutant huntingtin allele at a position on the allele comprising a single nucleotide polymorphism (SNP) site, wherein the compound administered to the subject treats, ameliorates and/or slows the onset and/or progression Huntington's Disease by selectively reducing the mutant huntingtin allele.
  • SNP single nucleotide polymorphism
  • the present disclosure pertains to: a method of ameliorating a symptom of Huntington’s disease, comprising administering a HTT oligonucleotide or HTT oligonucleotide composition to human subject in need thereof.
  • a HTT oligonucleotide is WVE-003.
  • a HTT oligonucleotide composition is a composition comprising WVE-003.
  • a WVE-003 composition is a chirally controlled oligonucleotide composition.
  • WVE-003 compositions are chirally controlled (e.g., stereopure) HTT oligonucleotide composition capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • WVE-003 can selectively targets one isoform of HTT SNP rs362273 (sometimes referenced as SNP3).
  • WVE-003 is fully complementary to the sequence of the SNP (and surrounding sequences) that it is targeting. As described herein, in various embodiments, WVE-003 is fully complementary to a mHTT transcript.
  • WVE-003 is fully complementary to a mHTT transcript, and is not fully complementary to a wtHTT transcript.
  • a mHTT transcript is associated with, or more associated with than a wtHTT transcript, a condition, disorder or disease like Huntington’s disease.
  • a mHTT comprises 36, 37, 38, 39, 40, 45, 50 or more CAG repeats.
  • complementary to a transcript may be assessed using genetic sequences from which a transcript is transcribed.
  • WVE-003 can be used as a disease-modifying agent for the treatment of subjects with Huntington’s disease (HD).
  • a composition of WVE-003 is a stereopure oligonucleotide composition which recognizes the disease-associated (e.g., mutant) allele of SNP rs362273 in the Huntingtin gene, is efficacious in reducing the level, expression and/or activity of a mHTT gene (or a gene product thereof), and is capable of mediating allele-specific knockdown of the mutant Huntingtin (mHTT) gene.
  • the present disclosure provides methods for reducing level, expression 5 of 265 12842751v1 Attorney Docket No.: 2010581-1510 and/or activity of a mHTT gene (or a gene product thereof), comprising administering to a subject an oligonucleotide at a dose or according to a dosage regimen as described herein.
  • level of mHTT transcripts is reduced.
  • level of mHTT proteins is reduced.
  • level, expression and/or activity of a wtHTT gene is not significantly reduced.
  • assessments are performed using a sample from a subject.
  • a subject in various methods herein is a human.
  • assessments are performed using a sample from a human subject who is susceptible to or suffering from a condition, disorder or disease associated with mutant HTT (e.g., Huntington’s disease).
  • assessments are performed using a patient sample.
  • a “patient sample” is any biological specimen from a patient.
  • the term sample includes, but is not limited to, biological fluids such as blood, serum, plasma, urine, cerebrospinal fluid (CFS), tears, saliva, lymph, dialysis fluid, lavage fluid, semen, and/or other liquid samples, as well as cells and tissues of biological origin.
  • assessments are performed using CSF samples.
  • assessments are performed using plasma samples.
  • assessments are performed using blood samples.
  • assessment are performed at suitable time point(s) as appreciated by those skilled in the art, e.g., after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 3, 4, 5, 6, 7, or 8 weeks, or about 3, 4, 5, or 6 or more months after administration of a dose and before a next dose, if any, is administered.
  • assessment is performed after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses are administered.
  • assessment results are for an individual subject.
  • assessment are performed on a population of subjects, e.g., as typically performed in clinical trials or in clinical applications.
  • a population has a size of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000 or more subjects.
  • the size is about 10 or more subjects.
  • the size is about 20 or more subjects.
  • the size is about 36 subjects.
  • the size is about 30 or more subjects.
  • the size is about 40 or more subjects.
  • the size is about 50 or more subjects.
  • the size is about 100 or more subjects.
  • the size is about 200 or more subjects.
  • the size is about 500 or more subjects.
  • the size is about 1000 or more subjects.
  • reduction is about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more. In some embodiments, it is at least about 10% or more. In some embodiments, it is at least about 12% or more. In some embodiments, it is at least about 20% or more. In some embodiments, it is at least about 30% or more. In some embodiments, it is at least about 40% or more. In some embodiments, it is at least about 50% or more.
  • a mHTT gene or product thereof comprises a sequence that is the same or fully complementary to WVE-003 sequence and contains expanded CAG repeats (or a sequence encoded thereby), and a wild-type HTT gene or product thereof does not contain a sequence that is the same or fully complementary to WVE-003 sequence in HTT or at rs362273 and contains fewer CAG repeats (e.g., not considered as expanded CAG repeats) (or a sequence encoded by the repeats).
  • a HTT oligonucleotide is WVE-003.
  • a composition is a composition comprising WVE-003.
  • a composition is a WVE-003 composition and substantially all oligonucleotides in the composition are WVE-003 (as appreciated by those skilled in the art, some other oligonucleotides may exist as impurities, levels of which can and are typically controlled in provided compositions).
  • a HTT oligonucleotide e.g., WVE-003, or composition is administered or delivered to a subject at a dose of about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10-160 mg, about 10-150 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg.
  • an amount of the present disclosure e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, 10-170 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg, is typically equivalent to free acid form of an oligonucleotide, unless explicitly noted otherwise.
  • WVE-003 is administered or delivered to a subject at a dose equivalent to about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10-160 mg, about 10-150 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg WVE-003 free acid form.
  • a dose is equivalent to about 10 mg WVE-003 free acid form.
  • a dose is equivalent to about 20 mg WVE- 003 free acid form.
  • a HTT oligonucleotide or composition is administered to a subject at a dosage of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg per month.
  • a HTT oligonucleotide or composition is administered to a subject at a dosage of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg every 8 weeks.
  • a HTT oligonucleotide or composition is administered to a subject at a dosage of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg every 12 weeks.
  • provided technologies provide long duration.
  • doses are administered every two months or less frequently.
  • doses are administered quarterly or less frequently.
  • the present disclosure pertains to: a method of treatment and/or prevention 9 of 265 12842751v1 Attorney Docket No.: 2010581-1510 of Huntington’s disease in a subject (e.g., a patient such as a human patient) in need thereof; a method of allele- specific knockdown of a mutant Huntingtin transcript in a subject; and/or a method for reducing the severity of and/or delaying the onset of one or more symptoms of Huntington’s disease, wherein the method comprises administering WVE-003 in multiple doses, each of which is independently equivalent to about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg WVE-003 free acid form.
  • a subject e.g., a patient such as a human patient
  • the method comprises administering W
  • the amount of each dose remains constant (e.g., each dose a patient receives is about 30 mg; or each dose a patient receives is about 60 mg; or each dose a patient receives is about 90 mg; or each dose a patient receives is about 120 mg); In some embodiments, the amount of each dose changes over time (e.g., a patient may be maintained for one or more doses at a particular dose, and later, due to efficacy and/or safety or other issues, the amount of each dose may be increased or decreased). In some embodiments, multiple doses are administered and each is independently about 30 mg WVE-003 free acid form. In some embodiments, multiple doses are administered approximately monthly or once approximately every 4 weeks.
  • the doses are administered approximately monthly or once approximately every 4 weeks, except for approximately two months or approximately eight weeks between the second and fourth doses.
  • multiple doses are administered once approximately every 8 weeks.
  • a method comprises administering multiple doses once approximately every 8 weeks, each of which is independently equivalent to about 30 mg WVE-003 free acid form.
  • multiple doses are administered once approximately every 12 weeks.
  • a method comprises administering multiple doses once approximately every 12 weeks, each of which is independently equivalent to about 30 mg WVE-003 free acid form.
  • each dose is administered as a pharmaceutical composition as described herein.
  • the doses are administered at least about 2 times.
  • the doses are administered at least about 3 times. In some embodiments, the doses are administered at least about 4 times. In some embodiments, interval between a dose and its immediate following dose is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In some embodiments, interval between each dose and its immediate following dose is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In some embodiments, an interval is about 1 week. In some embodiments, an interval is about 2 weeks. In some embodiments, an interval is about 3 weeks. In some embodiments, an interval is about 4 weeks.
  • an interval is about 5 weeks. In some embodiments, an interval is about 6 weeks. In some embodiments, an interval is about 7 weeks. In some embodiments, an interval is about 8 weeks. In some embodiments, an interval is about 9 weeks. In some embodiments, an interval is about 10 weeks. In some embodiments, an interval is about 11 weeks. In some embodiments, an interval is about 12 weeks. In some embodiments, an interval is about 1 month. In some embodiments, an interval is about 2 months. In some embodiments, an interval is about 3 or more months. In some embodiments, an interval is about 3, 4, 5, 10 of 265 12842751v1 Attorney Docket No.: 2010581-1510 6, 7, 8, or 9 months. In some embodiments, an interval is about 3 months.
  • an interval is about 6 months. In some embodiments, an interval is about 9 months. In some embodiments, each interval is independently about 1 or more weeks. In some embodiments, each interval is independently about 2 or more weeks. In some embodiments, each interval is independently about 3 or more weeks. In some embodiments, each interval is independently about 4 or more weeks. In some embodiments, each interval is independently about 5 or more weeks. In some embodiments, each interval is independently about 6 or more weeks. In some embodiments, each interval is independently about 7 or more weeks. In some embodiments, each interval is independently about 8 or more weeks. In some embodiments, each interval is independently about 9 or more weeks. In some embodiments, each interval is independently about 10 or more weeks. In some embodiments, each interval is independently about 11 or more weeks.
  • each interval is independently about 12 or more weeks. In some embodiments, each interval is independently about 1 or more months. In some embodiments, each interval is independently about 2 or more months. In some embodiments, each interval is independently about 3 or more months. In some embodiments, each interval is independently about 3, 4, 5, 6, 7, 8, or 9 months. In some embodiments, each interval is independently about 1 months. In some embodiments, each interval is independently about 2 months. In some embodiments, each interval is independently about 3 months. In some embodiments, each interval is independently about 6 months. In some embodiments, each interval is independently about 9 months. In some embodiments, all intervals are about the same. In some embodiments, one or more intervals are longer than others. In some embodiments, one or more intervals are shorter than others.
  • dose frequency for multiple or all doses is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In some embodiments, dose frequency for multiple or all doses is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In some embodiments, one or more loading doses are administered. In some embodiments, no loading doses are administered. [0029] In some embodiments, use of WVE-003 in various methods is tested in a clinical trial designated the SELECT-HD Phase 1b/2a trial.
  • SELECT-HD is a 1b/2a multicenter, randomized, double-blind, placebo- controlled study to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and clinical effects of WVE- 003 in adult patients with early-manifest Huntington’s disease (HD) who carry a targeted single nucleotide polymorphism (SNP) rs362273 (SNP3).
  • Period 1 of this study evaluates single ascending doses (SAD) of WVE-003.
  • Period 2 evaluates multiple ascending doses (MAD) of WVE-003.
  • a subject is with early manifest Huntington’s disease.
  • a subject is 25 years old or older.
  • a subject is 60 years old or younger.
  • an oligonucleotide e.g., WVE-003, or a composition is administered intrathecally.
  • intrathecal administration is interspinal administration.
  • a method described herein comprises administering a HTT oligonucleotide, e.g., WVE-003, or a composition thereof intrathecally and in an amount described herein, e.g., equivalent to about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 11 of 265 12842751v1 Attorney Docket No.: 2010581-1510 130, about 140, about 150, or about 168 mg oligonucleotide (e.g., WVE-003) free acid form.
  • a HTT oligonucleotide e.g., WVE-003
  • a composition thereof intrathecally in an amount described herein, e.g., equivalent to about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 11 of 265 12842751v1 Attorney Docket No.: 2010581
  • a method described herein comprises administering a HTT oligonucleotide (e.g., WVE-003) or a composition thereof intrathecally and each independently in an amount described herein, e.g., equivalent to about 10, about 20, about 30, about 60, about 90, about 120, about 150, or about 168 mg oligonucleotide (e.g., WVE-003) free acid form with dose intervals described herein, e.g., monthly.
  • an oligonucleotide, e.g., WVE-003, or a composition is administered by direct lumbar injection.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition elicits a desired biological response when administered as part of a therapeutic regimen.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is an amount (e.g., about 30, about 60, about 90, about 120, about 150, or about 168 mg free acid form) that is sufficient, when administered to a subject suffering from or susceptible to Huntington’s disease, to treat, prevent, and/or delay the onset of Huntington’s disease (e.g., at least one symptom of Huntington’s disease).
  • a method described herein comprises the step of administering a therapeutically effective amount of a HTT oligonucleotide or HTT oligonucleotide composition.
  • a HTT oligonucleotide or HTT oligonucleotide composition is or comprises WVE-003.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating a clinically significant amount of allele- specific knockdown of a mutant HTT transcript.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition does not significantly decrease the amount of wild-type Huntingtin transcript or a gene product thereof.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition does not decrease the amount of wild-type Huntingtin transcript or a gene product thereof to a level associated with a clinically-manifested adverse event or side effect.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is low enough to prevent or reduce the occurrence and/or reduce the severity of at least about one adverse event mediated by and/or associated with administration of the oligonucleotide or oligonucleotide composition to the subject.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is sufficient to mediate a clinically significant amount of allele-specific knockdown of a mutant HTT transcript in a subject, but is low enough to prevent or reduce the occurrence and/or reduce the severity of at least about one adverse event mediated by and/or associated with administration of the oligonucleotide or oligonucleotide composition to the subject.
  • an adverse event is an adverse effect. In some embodiments, an adverse event is mild, moderate, severe, or serious.
  • an adverse event is: pyrexia, headache, vomiting, or tachycardia.
  • an adverse event is or is, is measured by, or is related to an 12 of 265 12842751v1 Attorney Docket No.: 2010581-1510 increase in pro-inflammatory markers (e.g., C-reactive protein and complement), prolongation of aPTT, thrombocytopenia, liver enzyme changes (e.g., AST and ALT) or kidney biomarker changes (e.g., BUN, creatinine).
  • pro-inflammatory markers e.g., C-reactive protein and complement
  • prolongation of aPTT e.g., thrombocytopenia
  • liver enzyme changes e.g., AST and ALT
  • kidney biomarker changes e.g., BUN, creatinine
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is sufficient to achieve a clinically significant maximum plasma concentration of the HTT oligonucleotide or oligonucleotide composition.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 30 mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 60 mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 90 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 120 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 150 mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 168 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 30 +25% mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 60 +25% mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 90 +25% mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 120 +25% mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 150 +25% mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is 168 +25% mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 30 mg, about 60 mg, about 90 mg, about 120 mg, or about 150 mg (irrespective of body weight, as the total volume of the central nervous system is similar in most adult humans).
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 30 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 60 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 90 mg.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 120 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 150 mg. In some embodiments, a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is about 168 mg.
  • a HTT oligonucleotide is WVE-003.
  • the present disclosure provides methods comprising administering to a subject a HTT oligonucleotide or HTT oligonucleotide composition in an amount of about 30, about 60, about 90, about 120, about 150, or about 168 mg equivalent to the free acid form of the oligonucleotide.
  • the present disclosure provides methods comprising administering to a subject a HTT oligonucleotide or HTT oligonucleotide composition in an dose of about 30, about 60, about 90, about 120, about 150, or about 168 mg, wherein the oligonucleotide is WVE-003.
  • doses are administered approximately once a month, or approximately every four weeks.
  • doses are administered approximately once every two months, or approximately every eight weeks.
  • doses are administered approximately once every three months, or approximately every twelve weeks.
  • the time between the first and second doses is about 2 months or about 8 weeks, and each subsequent dose is administered approximately once a month, or approximately every four weeks.
  • a patient is maintained on the same dose or a constant dose (e.g., each dose a patient receives is 30 mg; or each dose a patient receives is 60 mg; or each dose a patient receives is 90 mg; or each dose a patient receives is 120 mg).
  • a patient receives multiple doses of different amounts. For example, a patient may receive one or more initial dose at a particular amount of HTT oligonucleotide or HTT oligonucleotide composition, and the subsequent doses the patient receives may be increased or decreased, due to efficacy, safety, or other issues.
  • the present disclosure recognizes challenges of providing oligonucleotides with high efficacy and low toxicity, and methods of use thereof.
  • the present disclosure provides oligonucleotide, e.g., WVE-003, and compositions and methods with reduced toxicity.
  • provided technologies provide reduced toxicity levels when about the same or comparable amount of oligonucleotides are delivered, and/or when about the same or comparable levels of desired effects and/or effects are achieved.
  • more oligonucleotide, e.g., WVE-003 can be delivered, and/or higher levels of desired effects and/or effects are achieved.
  • a reference oligonucleotide is a non-selective oligonucleotide. In some embodiments, a reference oligonucleotide has a different structure compared to WVE-003. In some embodiments, a reference oligonucleotide has the same base sequence but different structure compared to WVE-003. In some embodiments, a reference oligonucleotide comprises different modifications and/or 14 of 265 12842751v1 Attorney Docket No.: 2010581-1510 patterns thereof. In some embodiments, a reference oligonucleotide comprises different internucleotidic linkages and/or patterns thereof.
  • a reference oligonucleotide comprises different linkage stereochemistry or patterns thereof.
  • a reference oligonucleotide is provided as a stereorandom composition.
  • a reference oligonucleotide is provided as a chirally controlled oligonucleotide composition.
  • a reference oligonucleotide is of lower purity.
  • a reference oligonucleotide is of lower stereopurity.
  • a reference oligonucleotide is WV-1092. In some embodiments, a reference oligonucleotide is WV-2603.
  • the present disclosure provides oligonucleotide compositions and methods with reduced immune responses.
  • the present disclosure recognizes that various toxicities induced by oligonucleotides may be related to cytokine and/or complement activation.
  • a HTT oligonucleotide composition e.g., WVE-003
  • WVE-003 is chirally controlled (e.g., stereopure).
  • a stereorandom HTT oligonucleotide preparations contain a plurality of distinct chemical entities that differ from one another, e.g., in the stereochemical structure of individual backbone chiral centers (e.g., phosphorothioates) within the HTT oligonucleotide chain. Without control of stereochemistry of backbone chiral centers, stereorandom HTT oligonucleotide preparations provide uncontrolled (or stereorandom) compositions comprising undetermined levels of HTT oligonucleotide stereoisomers.
  • stereoisomers may have the same base sequence and/or chemical modifications, they are different chemical entities at least about due to their different backbone stereochemistry, and they can have, as demonstrated herein, different properties, e.g., activities, toxicities, distribution etc.
  • the present disclosure provides chirally controlled compositions that are or contain particular stereoisomers of HTT oligonucleotides of interest; in contrast to chirally uncontrolled compositions, chirally controlled compositions comprise controlled levels of particular stereoisomers of HTT oligonucleotides, or in a chirally controlled composition a controlled level of all oligonucleotides of the composition, or a controlled level of all oligonucleotides of the composition that share a particular base sequence (e.g., that of WVE-003) share a common pattern of linkage phosphorus stereochemistry configuration (e.g., that of WVE-003).
  • a controlled level of all oligonucleotides that share the same constitution as a form of WVE-003 are WVE-003.
  • diastereopurity of WVE-003 is about or above a controlled level.
  • a controlled level is at least about 10%. In some embodiments, a controlled level is at least about 20%. In some embodiments, a controlled level is at least about 25%. In some embodiments, a controlled level is at least about 30%. In some embodiments, a controlled level is at least about 40%. In some embodiments, a controlled level is at least about 50%. In some embodiments, a controlled level is at least about 60%. In some embodiments, a controlled level is at least about 70%.
  • a controlled level is at least about 75%. In some embodiments, a controlled level is at least about 80%. In some embodiments, a controlled level is at least about 85%. In some embodiments, a controlled level is at least about 90%. In some embodiments, a controlled level is at least about 95%. In some embodiments, a controlled level 15 of 265 12842751v1 Attorney Docket No.: 2010581-1510 is at least about 96%. In some embodiments, a controlled level is at least about 97%. In some embodiments, a controlled level is at least about 98%. In some embodiments, a controlled level is at least about 99%.
  • a therapeutically effective amount of a HTT oligonucleotide, a HTT oligonucleotide composition, WVE-003, is about 30, about 60, about 90, about 120, about 150 or about 168 mg.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is or comprises WVE-003, which is a chirally controlled HTT oligonucleotide composition capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • a HTT gene in a human subject is: (A) heterozygous at the CAG repeat (wherein one allele comprises a deleterious CAG repeat expansion and the other allele does not), and (B) heterozygous at a SNP targeted by a HTT oligonucleotide, wherein the HTT oligonucleotide is capable of differentiating between two alleles of the same SNP (e.g., due to a difference in the sequence of the SNP alleles); and (C) the deleterious CAG repeat is on the same chromosome as the SNP allele targeted by the HTT oligonucleotide; and such an arrangement is referenced as the CAG repeat expansion and the mutant SNP allele being in phase, and the HTT gene or a mutation thereof can be described as amenable to allele-specific knockdown.
  • a mutant HTT gene comprising a mutation that is amenable to an allele- specific knockdown of the mutant HTT gene is: a mutant HTT gene comprising a deleterious mutation (e.g., a CAG repeat expansion), wherein the deleterious mutation is on the same chromosome as (e.g., in phase with, or in the same phase as) a particular allele of a SNP which is targeted by a particular HTT oligonucleotide (e.g., WVE-003), wherein targeting by the oligonucleotide of the SNP allele also targets the deleterious mutation.
  • a deleterious mutation e.g., a CAG repeat expansion
  • the deleterious mutation is on the same chromosome as (e.g., in phase with, or in the same phase as) a particular allele of a SNP which is targeted by a particular HTT oligonucleotide (e.g., WVE-003), wherein targeting by
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject 16 of 265 12842751v1 Attorney Docket No.: 2010581-1510 WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • a subject is determined to express a mHTT transcript that is full complementary to the sequence an administered oligonucleotide, including at a SNP site (e.g., rs362273).
  • a subject is determined to have a mHTT allele that comprises the same sequence (as appreciated by those skilled in the art U and T may be properly considered the same) or is fully complementary to the sequence of an administered oligonucleotide, including at a SNP site (e.g., rs362273).
  • a subject is homozygous with respect to a SNP site and/or wild-type or mutant HTT.
  • a subject is heterozygous with respect to a SNP site and/or wild-type or mutant HTT.
  • a subject expresses a mHTT transcript that is fully complementary to an administered oligonucleotide, and a wtHTT transcript that is not fully complementary to an administered oligonucleotide.
  • a mHTT allele that is fully complementary to an administered oligonucleotide, and a wtHTT transcript that is not fully complementary to an administered oligonucleotide are available and can be utilized in accordance with the present disclosure to detect and/or determine if a particular isoform of a SNP is on the same allele or transcript.
  • the present disclosure provides for a method for determining the suitability of treatment of a subject for administration of WVE-003 (or a salt form thereof), said method comprising the steps of: 17 of 265 12842751v1 Attorney Docket No.: 2010581-1510 i) determining the presence of mutant allele in a patient with the targeted single nucleotide polymorphism (SNP) rs362273 (SNP3) versus the wild type allele; ii) comparing the level of mutant allele in a patient with the targeted single nucleotide polymorphism (SNP) rs362273 (SNP3) of step i) with one or more reference samples or reference values; iii) determining whether the subject is likely to be, or is suitable for, treatment with WVE-003, wherein the subject is suffering from or at risk of developing an neurodegenerative disorder, such as Huntington’s disease; and iv) administering an effective amount of WVE-003 to the subject
  • the present disclosure provides for the use of a phasing assay in the detection of the presence of a mutant allele in a patient with the targeted single nucleotide polymorphism (SNP) rs362273 (SNP3) versus the wild type allele to determine suitability of treatment with WVE-003.
  • SNP single nucleotide polymorphism
  • SNP3 targeted single nucleotide polymorphism rs362273
  • an HTT oligonucleotide that targets that SNP allele can also “target” the disease-associated CAG repeat expansion, thereby allowing a decrease in the expression, level and/or activity of the HTT allele with the disease-associated mutation.
  • an HTT oligonucleotide can be used in a treatment for an HTT-related disorder such as Huntington’s disease.
  • An HTT oligonucleotide targeting a SNP can thus preferentially decrease the expression, level and/or activity of a mutant allele of HTT compared to the wild-type allele.
  • Phasing data can be important in allele-specific therapies for diseases such as Huntington’s disease.
  • a genetic lesion such as a deleterious repeat, deletion, insertion, inversion or other mutation has been identified, such as an expanded CAG repeat expansion in mutant (and disease-associated) HTT alleles.
  • one allele of a gene such as HTT can comprise a disease-associated mutation at a genetic locus, while the other allele is normal, wild-type or otherwise not or less disease-associated.
  • an allele-specific therapy can target an allele of HTT comprising a disease-associated mutation, but not the corresponding wild-type allele.
  • an allele-specific therapy can target an HTT allele comprising a disease-associated mutation at a particular locus, such as a CAG repeat expansion (or expanded CAG tract), but not by directly targeting the locus, but rather by targeting a different locus on the mutant allele.
  • an allele-specific therapy can target an allele comprising a disease- 18 of 265 12842751v1 Attorney Docket No.: 2010581-1510 associated mutation at a locus by targeting a different locus in the same allele, such as a SNP (single nucleotide polymorphism) in the same gene.
  • a SNP single nucleotide polymorphism
  • some disease-associated genetic lesions may be difficult to target or otherwise not readily amenable to targeting.
  • mutant HTT comprise repeats (e.g., trinucleotide or tetranucleotide repeats); in some cases, such as Huntington’s disease, a small number of repeats is not disease-associated, but an abnormally large number of repeats, or a repeat expansion, is disease-associated. Because the repeats exist on both the wild-type and mutant alleles, it may be difficult to target the disease-associated repeats directly. However, if a particular SNP variant exists on the same allele as the disease-associated repeat expansion but not on the wild-type allele, that SNP variant can be used to target an allele-specific therapy which targets the mutant allele but not the wild-type allele.
  • repeats e.g., trinucleotide or tetranucleotide repeats
  • phasing data for an individual indicates if a particular SNP is in phase (e.g., on the same chromosome or transcript) as the lesion and thus that SNP can be targeted with a therapeutic nucleic acid.
  • the therapeutic can then target the mutant gene, while not targeting the wild-type allele.
  • Obtaining the phasing data to target only the mutant allele can be especially useful if expression of the wild- type allele is essential.
  • phasing information is useful if it is known that an individual has both a wild-type and a mutant allele of each of two genetic loci on the same gene.
  • the present disclosure presents, inter alia, various methods for phasing genetic loci on a nucleic acid template.
  • the present disclosure presents methods for phasing a genetic locus such as a genetic lesion (such as an inversion, fusion, deletion, insertion or other mutation) and another genetic locus (such as a SNP) on a chromosome; the two genetic loci can be in the same gene, or in different genes.
  • an example patient may have Huntington's Disease, which is linked to a mutation in the Huntingtin gene (HTT) comprising an excessive number of repeats (e.g., a repeat expansion) of the sequence CAG.
  • the patient may be under consideration for treatment with an allele-specific therapeutic (e.g., an antisense oligonucleotide or RNAi agent) which recognizes a particular allelic variant of a genetic locus in the HTT gene (which is outside the repeat expansion), as a non-limiting example, a SNP.
  • an allele-specific therapeutic e.g., an antisense oligonucleotide or RNAi agent
  • phasing reveals that the same chromosome of the patient comprises both the repeat expansion and the particular allelic variant of a genetic locus (e.g., a SNP) recognized by the allele-specific therapeutic, then the patient is eligible for treatment with the allele-specific therapeutic.
  • a genetic locus e.g., a SNP
  • Various methods for phasing are known in the art, including but not limited to those described in: WO2018/022473; and Berger et al. 2015 Res. Comp. Mol. Biol.9029: 28-29; Castel et al.2015 Genome Biol. 16: 195; Castel et al.
  • sequencing particularly sequencing that can produce long single reads, can be utilized for phasing.
  • Allele-specific PCR is a technique in which the variant of the nucleic acid sequence present in the PCR reaction mixture is selectively amplified and detected. Allele-specific PCR employs at least one "allele- specific primer.”
  • allele-specific primer generally refers to a primer whose extension occurs in a PCR reaction only when a specific variant of a nucleic acid sequence is present in the reaction mixture.
  • allele-specific primers are designed in such a way that they discriminate between variants of nucleic acids and selectively multiply nucleic acid templates that include a variant to be detected.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • nucleic acid sequences are detected by suitable methods, such as quantitative amplification and/or nucleic acid sequencing.
  • suitable methods such as quantitative amplification and/or nucleic acid sequencing.
  • Methods of quantitative amplification are disclosed in, e.g., U.S. Patent Nos. 5,210,015; 5,804,375; 6,127,155; 6,180,349; 6,033,854; and 5,972,602, as well as in, e.g., Holland et al, Proc. Natl. Acad. Sci.
  • Amplifications may be monitored in "real time.” Though standard Sanger dideoxy or other older nucleotide sequencing methods can be used, sequencing can be particularly effective when high throughput sequencing is used, e.g., "next generation sequencing” methods such as HiSeq TM , MiSeq TM , or Genome Analyzer (each available from Illumina), SOLiD TM or Ion Torrent TM (each available from Life Technologies) and 454 TM sequencing (from Roche Diagnostics). For example, in high-throughput sequencing, parallel sequencing reactions using multiple templates and multiple primers allows rapid sequencing of genomes or large portions of genomes.
  • the amplicons are sequenced by one of the methods selected from a base-incorporation method, e.g., a pyrosequencing method (U.S. Pat. Nos.6,274,320, 6,258,568 and 6,210,891); a hydrogen ion detection method (ISFET) (e.g., U.S. Pat. No. 8,262,900), or a dye-terminator detection method (U.S. Pat.
  • a base-incorporation method e.g., a pyrosequencing method (U.S. Pat. Nos.6,274,320, 6,258,568 and 6,210,891)
  • ISFET hydrogen ion detection method
  • U.S. Pat. No. 8,262,900 e.g., U.S. Pat. No. 8,262,900
  • dye-terminator detection method U.S. Pat.
  • Deep sequencing technology and instruments e.g., technology and instrument capable of digital sequence readout
  • instruments include GS family of instruments (454 Life Sciences, Branford, Conn.); ION PROTON * and PGM TM (Life Technologies, Grand Island, N.Y.); HISEQ * and MISEQ * (Illumina, San Diego, Cal.) or any improvements and modifications of thereof.
  • a sequencing technology is or comprises long-read sequencing.
  • a long-read sequencing covers two or more sequence elements, for example, in some embodiments, one is a SNP and the other is a mutation (e.g., a point mutation, a CAG repeat, etc.).
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with 21 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with 22 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 at a dose of about 60 mg.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) 23 of 265 12842751v1 Attorney Docket No.: 2010581-1510 at a dose of about 120 mg.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg.
  • the present disclosure pertains to: A method delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg.
  • an amount of WVE-003 typically include all forms of WVE-003 being administered but all converted to the amount of the acid form.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered a steroid at least about one month prior to the first dose of WVE-003. [0088] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered WVE-003 approximately monthly for at least about 4 months. [0089] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered WVE-003 approximately monthly for at least about 8 months.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered the oligonucleotide approximately monthly for at least about 12 months. [0091] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered the oligonucleotide approximately monthly for at least about 16 months. [0092] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the subject is administered the oligonucleotide approximately monthly for at least about 48 months.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is delivered intrathecally. [0094] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific knockdown of the mutant HTT gene or a gene product 24 of 265 12842751v1 Attorney Docket No.: 2010581-1510 thereof transcript. [0095] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation.
  • the method includes the step of lyophilization (e.g., freeze-drying or freeze- drying under a vacuum).
  • lyophilization e.g., freeze-drying or freeze- drying under a vacuum.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation reconstituted from a lyophilized (e.g., freeze-dried) preparation of the oligonucleotide.
  • the present disclosure pertains to: a lyophilized (e.g., freeze-dried) preparation of WVE-003.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation, wherein the liquid formulation comprises the oligonucleotide, sodium chloride and water. [0100] In some embodiments, the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation with a solution of sodium chloride.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation with a solution of 0.9% sodium chloride.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation with a solution of sterile sodium chloride.
  • the present disclosure pertains to: The method of any of the previous embodiments, wherein the oligonucleotide is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation with 0.9% sterile sodium chloride.
  • a lyophilized preparation of WVE-003 is a dry (or dried) solid.
  • a lyophilized preparation of WVE-003 is a dry powder.
  • a lyophilized preparation of WVE-003 is a dry powder prepared by lyophilization of a liquid formulation of WVE-003 in water.
  • a lyophilized preparation of WVE-003 is a dry powder in a single-use clear glass vial. [0108] In some embodiments, a lyophilized preparation of WVE-003 is about 20 mg of a dry powder in a vial. [0109] In some embodiments, a lyophilized preparation of WVE-003 is a dry powder in a 10 mL vial. [0110] In some embodiments, a lyophilized preparation of WVE-003 is about 20 mg of a dry powder in a 10 mL vial.
  • the subject is administered a steroid prior to the first dose of WVE-003.
  • the subject is administered a steroid at least about one month prior to the first dose of WVE-003.
  • the subject is administered a dose of WVE-003 approximately once a month, or approximately every four weeks.
  • the subject is administered a dose of WVE-003 approximately once every two months or approximately every eight weeks.
  • the subject is administered a dose of WVE-003 approximately once a month, or approximately every four weeks, except that the time between the first and second doses is about 2 months or about 8 weeks, and each subsequent dose is administered approximately once a month, or approximately every four weeks.
  • the subject is administered a dose of WVE-003 approximately once every two months, or approximately every 8 weeks, except that the time between the first and second doses is about 3 months or about 12 weeks, and each subsequent dose is administered approximately once every two months, or approximately every 8 weeks.
  • the subject is administered WVE-003 approximately every 8 weeks for at least about 16 weeks.
  • the subject is administered WVE-003 approximately every 12 weeks for at least about 12 weeks. In some embodiments, about or at least about 2, 3, 4, 5, 6, 7, 8, 9 or 10 consecutive doses are administered approximately every 12 weeks. [0119] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 4 months. [0120] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 8 months. [0121] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 12 months. [0122] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 16 months.
  • the subject is administered WVE-003 approximately monthly for at least about 48 months.
  • the subject is administered a steroid prior to the first dose of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is administered a steroid at least about one month prior to the first dose of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is administered hydrocortisone and/or acetaminophen within 24 hours of administration of a HTT oligonucleotide or a HTT oligonucleotide composition. 26 of 265 12842751v1 Attorney Docket No.: 2010581-1510 [0127] In some embodiments, the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 8 months. [0128] In some embodiments, the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 12 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 16 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 48 months.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript.
  • the present disclosure provides a pharmaceutical composition comprising a HTT oligonucleotide or a HTT oligonucleotide composition of the present disclosure (e.g., WVE-003 ) and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject, comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing protein level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject, comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for slowing caudate atrophy, comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for reducing Total Motor Score (TMS) of a subject suffering from Huntington’s disease, comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • TMS Total Motor Score
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a subject, comprising administering or delivering to the subject WVE- 003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and 28 of 265 12842751v1 Attorney Docket No.: 2010581-1510 the regimen comprises a set of two or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks or less frequently.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects, comprising administering or delivering WVE- 003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for slowing caudate atrophy in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for reducing Total Motor Score (TMS) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • each dose of WVE-003 is independently equivalent to about 30 mg WVE- 003 free acid form.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject, comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing protein level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject, comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for slowing caudate atrophy, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for reducing Total Motor Score 30 of 265 12842751v1 Attorney Docket No.: 2010581-1510 (TMS) of a subject suffering from Huntington’s disease, comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • TMS Total Motor Score 30 of 265 12842751v1 Attorney Docket No.: 2010581-1510
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a subject, comprising administering or delivering to the subject WVE- 003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 8 weeks or less frequently; and the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 8 weeks or less frequently; and the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and the regimen comprises a set of two or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks or less frequently.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and 31 of 265 12842751v1 Attorney Docket No.: 2010581-1510 each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects, comprising administering or delivering WVE- 003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for slowing caudate atrophy in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for reducing Total Motor Score (TMS) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • TMS Total Motor Score
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject, comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing protein level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject, comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a subject, comprising administering or delivering to the subject WVE- 003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 12 weeks or less frequently, 33 of 265 12842751v1 Attorney Docket No.: 2010581-1510 wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and the regimen comprises a set of two or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks or less frequently.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects, comprising administering or delivering WVE- 003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; and each subject of the population independently has the A variant of rs362273 on the same allele as an 34 of 265 12842751v1 Attorney Docket No.: 2010581-1510 expanded CAG repeat region in a HTT gene.
  • each dose of WVE-003 is independently equivalent to about 30 mg WVE- 003 free acid form.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject, comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method for selectively reducing protein level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject, comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a subject, comprising administering or delivering to the subject WVE- 003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and the subject has a mutant HTT gene encoding mutant HTT protein comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 12 weeks or less frequently; and the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 12 weeks or less frequently; and the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and the regimen comprises a set of two or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks or less frequently.
  • the present disclosure provides a method, comprising administering or delivering WVE-003 to a population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the present disclosure provides a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects, comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • CSF cerebrospinal fluid
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects, comprising administering or delivering WVE- 003 to the population of subjects, wherein: 36 of 265 12842751v1 Attorney Docket No.: 2010581-1510 each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; and each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • the number of doses in a set is 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. In some embodiments, the number of doses in a set is 3, 4, 5, 6, 7, 8, 9, 10 or more. In some embodiments, the number of doses in a set is 2. In some embodiments, the number of doses in a set is 3. In some embodiments, one or more doses are administered or delivered prior to the set of doses, and/or one or more doses are administered or delivered subsequent to the set of doses. In some embodiments, two or more doses in a set are administered or delivered about every 8 weeks. In some embodiments, three or more doses in a set are administered or delivered about every 8 weeks.
  • all doses in a set are administered or delivered about every 8 weeks. In some embodiments, two or more doses in a set are administered or delivered less frequently than about every 8 weeks, e.g., about every 9, 10, 11, or 12 weeks, about quarterly, etc. In some embodiments, two or more doses in a set are administered or delivered about every 12 weeks. In some embodiments, three or more doses in a set are administered or delivered about every 12 weeks. In some embodiments, all doses in a set are administered or delivered about every 12 weeks. In some embodiments, two or more doses in a set are administered or delivered about quarterly. In some embodiments, three or more doses in a set are administered or delivered about quarterly.
  • the present disclosure provides a pharmaceutical composition comprising a HTT oligonucleotide or a HTT oligonucleotide composition of the present disclosure (e.g., WVE-003), which can be utilized in pharmaceutical compositions by combining such oligomeric compounds with a suitable pharmaceutically acceptable diluent or carrier.
  • a pharmaceutically acceptable diluent includes phosphate- buffered saline (PBS).
  • PBS is a diluent suitable for use in compositions to be delivered parenterally.
  • a pharmaceutical composition comprising a HTT oligonucleotide or a HTT oligonucleotide composition of the present disclosure (e.g., WVE-003), and a pharmaceutically acceptable diluent.
  • the pharmaceutically acceptable diluent is PBS.
  • the pharmaceutically acceptable diluent is artificial CSF (aCSF).
  • pharmaceutical compositions are administered both directly to the CSF (e.g., IT and/or ICV injection and/or infusion) and systemically.
  • the present disclosure provides a method for allele-specific knockdown of a target HTT transcript, comprising the step of administering a HTT oligonucleotide composition of the present disclosure.
  • the present disclosure provides a method for reducing level of a HTT transcript or a product thereof, comprising the step of administering a HTT oligonucleotide composition of the 37 of 265 12842751v1 Attorney Docket No.: 2010581-1510 present disclosure.
  • a method for treating Huntington’s disease comprising the step of administering to a subject susceptible thereto or suffering therefrom a composition described in the present disclosure.
  • the present disclosure provides a method for treating Huntington’s disease, comprising the step of administering to a subject susceptible thereto or suffering therefrom a composition comprising any HTT oligonucleotide disclosed herein.
  • the present disclosure provides a method for treating Huntington’s disease, comprising (a) administering to a subject susceptible thereto or suffering therefrom a composition comprising any HTT oligonucleotide disclosed herein, and (b) administering to the subject additional treatment which is capable of preventing, treating, ameliorating or slowing the progress of Huntington’s disease.
  • the present disclosure provides a method comprising administering to a subject WVE-003, wherein the subject is determined to have a genetic sequence that is the same or fully complementary to the base sequence of WVE-003. In some embodiments, the present disclosure provides a method comprising administering to a subject WVE-003, wherein the subject is determined to have a genetic sequence that comprises a sequence that is the same or fully complementary to the base sequence of WVE-003 and a sequence that is or encodes an expanded CAG repeats.
  • the present disclosure provides a method comprising administering to a subject WVE-003, wherein the subject is determined to have a genetic sequence that encodes a transcript that comprises an expanded CAG repeat in HTT and is fully complementary to the base sequence of WVE-003.
  • the present disclosure provides a method comprising administering to a subject WVE-003, wherein the subject is determined to express a HTT transcript that comprises an expanded CAG repeat and is fully complementary to the base sequence of WVE-003.
  • the present disclosure also provides various formulations of a HTT oligonucleotide or HTT oligonucleotide composition, any of which can be used in any method described herein.
  • the level, expression and/or activity of mutant HTT (e.g., a transcript and/or a gene product thereof) is reduced by at least about 5%.
  • the level, expression and/or activity of mutant HTT (e.g., a transcript and/or a gene product thereof) is reduced by at least about 10%.
  • Allele-selective lowering of mHTT protein with WVE-003 preserves wtHTT.
  • Doses of WVE-003 (30 mg) were administered on Days 1, 57, and 113. On Day 113, from top to bottom: WVE-003 30 mg and placebo. On Day 197, from top to bottom: placebo and WVE-00330 mg.
  • FIG. 1 Plasma neurofilament light (NfL) levels from cohorts receiving 3 doses of WVE-003 30 mg or placebo. On Day 29, from top to bottom: placebo and WVE-00330 mg. On Day 113, from top to bottom: WVE-00330 mg and placebo. On Day 169, from top to bottom: placebo and WVE-00330 mg. ** p ⁇ 0.01. [0214] Figure 17. Change in caudate volume at day 169 (8 weeks post last dose) from baseline from cohorts receiving 3 doses of WVE-00330 mg or placebo. Data from left to right: placebo and WVE-00330 mg. [0215] Figure 18.
  • FIG. 1 Example models of levels of mHTT protein in CSF in a cohort receiving 30 mg WVE- 003 Q8W (left graph) and 30 mg WVE-003 Q12W (right graph). Median predicted individual mHTT ratio as compared to baseline is graphed as a line. A 90% prediction interval is depicted as an area surrounding the line.
  • Figure 20 Example model of levels of mHTT protein in CSF in a cohort receiving 30 mg WVE- 003 Q12W.
  • the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term 40 of 265 12842751v1 Attorney Docket No.: 2010581-1510 “another” may be understood to mean at least an additional/second one or more; and (v) where ranges are provided, endpoints are included.
  • oligonucleotides and elements thereof e.g., base sequence, sugar modifications, internucleotidic linkages, linkage phosphorus stereochemistry, etc.
  • description of oligonucleotides and elements thereof is from 5’ to 3’.
  • oligonucleotides described herein may be provided and/or utilized in salt forms, particularly pharmaceutically acceptable salt forms.
  • oligonucleotides may be provided as salts, but are not limited to, e.g., sodium or potassium salts.
  • individual internucleotidic linkages along an oligonucleotide chain may be in an acid (H) form, or in one of a plurality of possible salt forms (e.g., a sodium salt, or a salt of a different cation, depending on which ions might be present in the preparation or composition)), and will understand that, so long as their acid forms (e.g., replacing all cations, if any, with H) are of the same constitution and/or structure, such individual oligonucleotides may properly be considered to be of the same constitution and/or structure.
  • H acid
  • salt forms e.g., a sodium salt, or a salt of a different cation, depending on which ions might be present in the preparation or composition
  • Dosing regimen As used herein, a “dosing regimen” or “therapeutic regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts.
  • a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount.
  • a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount.
  • pharmaceutical composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • 41 of 265 12842751v1 Attorney Docket No.: 2010581-1510 active agent is present in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a controlled therapeutic effect when administered to a relevant population.
  • compositions or vehicles which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • a provided compound comprises more than one acid groups, for example, a provided oligonucleotide may comprise two or more acidic groups (e.g., in natural phosphate linkages and/or modified internucleotidic linkages).
  • a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different.
  • each acidic group having sufficient acidity independently exists as its salt form (e.g., in an oligonucleotide comprising natural phosphate linkages and phosphorothioate internucleotidic linkages, each of the natural phosphate linkages and phosphorothioate internucleotidic linkages independently exists as its salt form).
  • a pharmaceutically acceptable salt of an oligonucleotide is a sodium salt of a provided oligonucleotide.
  • a pharmaceutically acceptable salt of an oligonucleotide is a sodium salt of a provided oligonucleotide, wherein each acidic linkage, e.g., each natural phosphate linkage and phosphorothioate internucleotidic linkage, exists as a sodium salt form (all sodium salt).
  • each acidic linkage e.g., each natural phosphate linkage and phosphorothioate internucleotidic linkage
  • each acidic linkage e.g., each natural phosphate linkage and phosphorothioate internucleotidic linkage
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and/or chemical phenomena.
  • Suffering from An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of a disease, disorder, and/or condition.
  • Susceptible to An individual who is “susceptible to” a disease, disorder, and/or condition is one who has a higher risk of developing the disease, disorder, and/or condition than does a member of the general public.
  • an individual who is susceptible to a disease, disorder and/or condition may not have been diagnosed with the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • Systemic The phrases “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” as used herein have their art-understood meaning referring to administration of a compound or composition such that it enters the recipient’s system.
  • Therapeutic agent refers to any agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect.
  • a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Therapeutically effective amount means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or 43 of 265 12842751v1 Attorney Docket No.: 2010581-1510 features of the disease, disorder, and/or condition.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • a single dose is an infusion, which may take up to one or more hours.
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Chirally controlled oligonucleotide composition refers to a composition that comprises a plurality of oligonucleotides (or nucleic acids, chirally controlled oligonucleotides or chirally controlled nucleic acids) which share 1) a common base sequence, 2) a common pattern of backbone linkages; 3) a common pattern of backbone chiral centers, and 4) a common pattern of backbone phosphorus modifications (oligonucleotides of a particular type), wherein the plurality of oligonucleotides (or nucleic acids) share the same stereochemistry at one or more chiral internucleotidic linkages (chirally controlled internucleotidic linkages, whose chiral linkage phosphorus is Rp or Sp,
  • Level of the plurality of oligonucleotides (or nucleic acids) in a chirally controlled oligonucleotide composition is non-random (pre-determined, controlled).
  • Chirally controlled oligonucleotide compositions are typically prepared through chirally controlled oligonucleotide preparation to stereoselectively form one or more chiral internucleotidic linkages (e.g., using chiral auxiliaries as exemplified in the present disclosure, compared to non-chirally controlled (stereorandom, non-stereoselective, racemic) oligonucleotide synthesis such as traditional phosphoramidite-based oligonucleotide synthesis using no chiral auxiliaries or chiral catalysts to purposefully control stereoselectivity).
  • a chirally controlled oligonucleotide composition is enriched, relative to a substantially racemic preparation of oligonucleotides having the common base sequence, the common pattern of backbone linkages, and the common pattern of backbone phosphorus modifications, for oligonucleotides of the plurality.
  • a chirally controlled oligonucleotide composition comprises a plurality of oligonucleotides of a particular oligonucleotide type defined by: 1) base sequence; 2) pattern of backbone linkages; 3) pattern of backbone chiral centers; and 4) pattern of backbone phosphorus modifications, wherein it is enriched, relative to a substantially racemic preparation of oligonucleotides having the same base sequence, pattern of backbone linkages, and pattern of backbone phosphorus modifications, for oligonucleotides of the particular oligonucleotide type.
  • each chirally controlled internucleotidic linkage independently has a diastereopurity of at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with respect to its chiral linkage phosphorus.
  • each independently has a diastereopurity of at least 90%.
  • each independently has a diastereopurity of at least 95%. In some embodiments, each independently has a diastereopurity of at least 97%. In some embodiments, each independently has a diastereopurity of at least 98%. In some embodiments, oligonucleotides of a plurality have the same constitution. In some embodiments, oligonucleotides of a plurality have the same constitution and stereochemistry, and are structurally identical.
  • the plurality of oligonucleotides in a chirally controlled oligonucleotide composition share the same base sequence, the same, if any, nucleobase, sugar, and internucleotidic linkage modifications, and the same stereochemistry (Rp or Sp) independently at linkage phosphorus chiral centers of one or more chirally controlled internucleotidic linkages, though stereochemistry of certain linkage phosphorus chiral centers may differ.
  • about 0.1%-100% (e.g., about 1%-100%, 5%-100%, 10%- 100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95- 100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition are oligonucleotides of the plurality.
  • about 0.1%-100% (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition that share the common base sequence are oligonucleotides of the plurality.
  • about 0.1%-100% (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%- 100%, 30%-100%, 40%-100%, 50%-100%, 60%-100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition that share the common base sequence, the common pattern of backbone linkages, and the common pattern of backbone phosphorus modifications are oligonucleotides of the plurality.
  • about 0.1%- 100% (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%- 100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of all oligonucleotides in a chirally controlled oligonucleotide composition, or of all oligonucleotides in a composition that share a common base sequence (e.g., of a plurality of oligonucleotide or an chirally controlled oli
  • a percentage is at least (DP) NCI , wherein DP is a percentage selected from 85%-100%, and NCI is the number of chirally controlled internucleotidic linkage.
  • DP is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • DP is at least 85%.
  • DP is at least 90%.
  • DP is at least 95%.
  • DP is at least 96%.
  • DP is at least 97%.
  • DP is at least 98%.
  • DP is at least 99%.
  • DP reflects diastereopurity of linkage phosphorus chiral centers chirally controlled internucleotidic linkages.
  • diastereopurity of a linkage phosphorus chiral center of an internucleotidic linkage may be typically assessed using an appropriate dimer comprising such an internucleotidic linkage and the two nucleoside units being linked by the internucleotidic linkage.
  • the plurality of oligonucleotides share the same stereochemistry at about 1-50 (e.g., about 1-10, 1-20, 5-10, 5-20, 10-15, 10-20, 10-25, 10-30, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) chiral internucleotidic linkages.
  • 1-50 e.g., about 1-10, 1-20, 5-10, 5-20, 10-15, 10-20, 10-25, 10-30, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20
  • the plurality of oligonucleotides share the same stereochemistry at about 0.1%- 100% (e.g., about 1%-100%, 5%-100%, 10%-100%, 20%-100%, 30%-100%, 40%-100%, 50%-100%, 60%- 100%, 70%-100%, 80-100%, 90-100%, 95-100%, 50%-90%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%) of chiral internucleotidic linkages.
  • each chiral internucleotidic linkage is a chiral controlled internucleotidic linkage, and the composition is a completely chirally controlled oligonucleotide composition.
  • not all chiral internucleotidic linkages are chiral controlled internucleotidic linkages, and the composition is a partially chirally controlled oligonucleotide composition.
  • a chirally controlled oligonucleotide composition comprises predetermined levels of individual oligonucleotide or nucleic acids types.
  • a chirally controlled oligonucleotide composition comprises one oligonucleotide type at a predetermined level (e.g., as described above). In some embodiments, a chirally controlled oligonucleotide composition comprises more than one oligonucleotide type, each independently at a predetermined level. In some embodiments, a chirally controlled oligonucleotide composition comprises multiple oligonucleotide types, each independently at a predetermined level.
  • a chirally controlled oligonucleotide composition is a composition of oligonucleotides of an oligonucleotide type, which composition comprises a predetermined level of a plurality of oligonucleotides of 46 of 265 12842751v1 Attorney Docket No.: 2010581-1510 the oligonucleotide type.
  • the present disclosure pertains to, inter alia, oligonucleotide compositions, oligonucleotide drug products, and methods thereof (e.g., WVE-003, an oligonucleotide composition thereof, a chirally controlled oligonucleotide composition thereof, or a therapeutically effective amount thereof, manufacturing methods thereof, therapeutic methods thereof, etc.) for treatment of Huntington’s disease (HD) or a symptom thereof.
  • WVE-003 an oligonucleotide composition thereof, a chirally controlled oligonucleotide composition thereof, or a therapeutically effective amount thereof, manufacturing methods thereof, therapeutic methods thereof, etc.
  • HD Huntington’s disease
  • the present disclosure pertains to WVE-003, and compositions and methods thereof.
  • a dosing regimen pertains to: the amount of an individual dose of an oligonucleotide, an oligonucleotide composition, a chirally controlled oligonucleotide composition, or a therapeutically effective amount of an oligonucleotide, an oligonucleotide composition, a chirally controlled oligonucleotide composition; and/or the interval between multiple or successive doses thereof; and/or the total length or duration of time during which a subject receives one or more doses thereof; and/or a particular formulation thereof.
  • the present disclosure provides technologies, e.g., oligonucleotides, compositions, methods, etc., related to the Huntingtin (HTT) gene or a product encoded thereby (a transcript, a protein (e.g., various variants of the Huntingtin protein, etc.).
  • the present disclosure provides technologies, including HTT oligonucleotides and compositions and methods thereof, for treatment of Huntington’s disease.
  • HTT comprises one or more mutations. In some embodiments, such mutations are associated with reduced biological functions of Huntingtin protein in a subject suffering from and/or susceptible to Huntington’s disease.
  • HTT Huntingtin
  • HTT refers to a gene or a gene product thereof (including but not limited to, a nucleic acid, including but not limited to a DNA or RNA, or a wild-type or mutant protein encoded thereby), from any species, and which may be also known as: HTT, HD, IT15, huntingtin, Huntingtin, or LOMARS; External IDs: OMIM: 613004, MGI: 96067, HomoloGene: 1593, GeneCards: HTT; Species: Human: Entrez: 3064; Ensembl: ENSG00000197386; UniProt: P42858; RefSeq (mRNA): NM_002111; 47 of 265 12842751v1 Attorney Docket No.: 2010581-1510 RefSeq (protein): NP_002102; Location (UCSC): Chr 4: 3.04 – 3.24 Mb; Species: Mouse: Entrez: 15194; En
  • HTT is a human or mouse HTT, which is wild-type or mutant.
  • a HTT protein is unmodified or modified.
  • a HTT protein has any one or more modifications of: 9 N6-acetyllysine; 176 N6-acetyllysine; 234 N6-acetyllysine; 343 N6-acetyllysine; 411 Phosphoserine; 417 Phosphoserine; 419 Phosphoserine; 432 Phosphoserine; 442 N6- acetyllysine; 640 Phosphoserine; 643 Phosphoserine; 1179 Phosphoserine; 1199 Phosphoserine; 1870 Phosphoserine; and/or 1874 Phosphoserine.
  • a mutation in HTT is reportedly a key factor in diseases and disorders such as Huntington’s disease.
  • a mutant HTT is designated mHTT, muHTT, m HTT, mu HTT, MU HTT, or the like, wherein m or mu indicate mutant.
  • a wild-type HTT is designated wild-type HTT, wtHTT, wt HTT, WT HTT, WTHTT, or the like, wherein wt indicates wild-type.
  • a mutant HTT comprises an expanded CAG repeat region (as appreciated by those skilled in the art, the number of CAG repeats may vary from subject to subject; e.g., in some embodiments, comprising 36 or more CAG repeats). In some embodiments, the number of CAG in a repeat is about 36. In some embodiments, the number of CAG in a repeat is about 38. In some embodiments, the number of CAG in a repeat is about 40. In some embodiments, the number of CAG in a repeat is about 41. In some embodiments, the number of CAG in a repeat is about 42.
  • a mutant HTT comprises a mutant allele of one or more SNP (the allele on the same DNA strand or chromosome as the expanded CAG repeat region).
  • wild-type HTT are reported to frequently have about or no more than about 18 CAG repeats, and mutant HTT are reported to frequently have about or more than about 43 CAG repeats.
  • heterozygosity of SNP rs362273 was identified in about 71% individuals.
  • SNP3 is associated with mHTT in about 40-45% of patients with HD.
  • a mutant HTT comprises both an expanded CAG repeat region and a mutant allele of a particular SNP on the same chromosomal strand.
  • the mutant allele of a particular SNP is targeted by a HTT oligonucleotide (e.g., WVE-003) and the mutant allele is on the same chromosome as the deleterious CAG repeat expansion, the oligonucleotide is capable of targeting the deleterious HTT allele and mediating allele-specific knockdown.
  • a human HTT is designated hHTT.
  • a mutant HTT is designated mHTT.
  • a mouse HTT when a mouse is utilized, a mouse HTT may be referred to as mHTT as those skilled in the art will appreciate.
  • 48 of 265 12842751v1 Attorney Docket No.: 2010581-1510 [0249]
  • wtHTT protein is critical for normal neuronal function and loss of wtHTT can contribute to cellular dysfunction. It has been reported that mHTT protein can have a detrimental effect on wtHTT protein function.
  • lowering mHTT can restore physiological control over HTT gene expression and/or relieve its detrimental effect on wtHTT functions, which have been reported to be involved in trafficking, gene expression, DNA repair, neuronal repair and/or regeneration, ciliogenesis, mitosis, CSF, etc.
  • mHTT can sequester wtHTT.
  • wtHTT is crucial for cilia health, and in the absence of HTT, ciliogenesis can fail, disrupting CSF flow and/or causing hydrocephalus.
  • allele-selective technologies can ameliorate both loss- of-function and gain-of-function disruptions caused by mHTT.
  • the provided disclosure provides technologies for reducing mHTT level. In some embodiments, the provided disclosure provides technologies for maintaining or increasing wtHTT level while reducing mHTT level. In some embodiments, the present disclosure provides technologies for reducing wtHTT sequestering by mHTT. In some embodiments, the present disclosure provides technologies for reducing level of wtHTT sequestered by mHTT. In some embodiments, the present disclosure provides improving or restoring a wtHTT function, e.g., through allele-selective reduction of mHTT level.
  • an oligonucleotide capable of mediating allele-specific knockdown of a mutant HTT gene or a gene product thereof is WVE-003.
  • Huntington’s disease Compositions comprising one or more HTT oligonucleotides described herein can be used to treat Huntington’s disease or a symptom thereof.
  • Huntington’s disease (HD) is reportedly a neurodegenerative disorder reportedly caused by a mutation of the HTT (huntingtin) gene. Alteration of this widely expressed single gene reportedly results in a progressive, neurodegenerative disorder with a large number of characteristic symptoms.
  • Huntington’s disease is reportedly a rare, progressive neurological disease that results in motor, cognitive, and psychiatric disability and is invariably fatal. Bates G, Tabrizi S, Jones L, (editors). Huntington's Disease, 4th Edition. Oxford (UK): Oxford University Press; 2014. Because it is a genetic, hereditary disease, it can reportedly affect multiple family members across generations. Sturrock A et al. J Geriatr Psychiatry Neurol. 2010;23(4): 243-259. Although cognitive and psychiatric symptoms may reportedly develop first, the clinical diagnosis of HD is usually based on the presence of chorea, one of the most visually prominent symptoms of this disease.
  • Chorea is reportedly an abnormal involuntary movement disorder, which occurs in 90% of subjects and is moderate to severe in approximately 70% of these subjects. These physical symptoms can reportedly appear at any age, but typically appear between the ages of 30 and 50.
  • HD Some of the symptoms of HD can reportedly be managed with medication and therapies such as antipsychotics and drugs affecting the dopamine pathways, which modulate the movement disorder.
  • Huntington’s disease is reportedly caused by a known mutation on a single gene, an expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the Huntingtin (HTT) gene.
  • CAG cytosine-adenine-guanine
  • HTT Huntingtin
  • a HD-related mutation is an expansion of a CAG repeat region in the HTT gene, wherein a larger expansion reportedly results in greater severity of the disease and an earlier age of onset.
  • the mutation reportedly results in a variety of motor, emotional and cognitive symptoms, and results in the formation of huntingtin aggregates in brain.
  • the CAG expansion reportedly results in the expansion of a poly-glutamine (poly-Q) tract in the huntingtin protein, a 350 kDa protein (Huntington Disease Collaborative Research Group, 1993. Cell. 72:971- 83).
  • a CAG repeat expansion is reportedly associated with Huntington’s disease.
  • Huntington’s disease has been reported to be an autosomal dominant disorder, with an onset generally in mid-life, although cases of onset from childhood to over 70 years of age have been documented. An earlier age of onset is reportedly associated with paternal inheritance, with 70% of juvenile cases being inherited through the father.
  • symptoms of Huntington’s disease have an emotional, motor and/or cognitive component.
  • One symptom, chorea is a characteristic feature of the motor disorder and is defined as excessive spontaneous movements which are irregularly timed, randomly distributed and abrupt. It can vary from being barely perceptible to severe. Other frequently observed abnormalities include dystonia, rigidity, bradykinesia, ocularmotor dysfunction, tremor, etc.
  • Voluntary movement disorders as symptoms include fine motor incoordination, dysarthria, and dysphagia. Emotional disorders commonly include depression and irritability, and cognitive component comprises subcortical dementia (Mangiarini et al.1996. Cell 87:493-506). It is reported that changes in HD brains are widespread and include neuronal loss and gliosis, particularly in the cortex and striatum (Vonsattel and DiFiglia.1998. J. Neuropathol. Exp. Neurol.57:369-384). [0261] In some embodiments, Huntington’s disease phenotypes range from mild HTT to severe, depending on the length of the CAG repeat expansion.
  • Huntington’s disease can be a devastating neurological disorder caused by a toxic gain of function and concurrent loss of function. Huntington’s disease is reported to be a monogenic autosomal dominant genetic disease that can be fully penetrant and affects entire brain.
  • HTT huntingtin protein
  • wtHTT huntingtin protein
  • the HD-ISS characterizes individuals for research purposes from birth, starting at Stage 0 (i.e., individuals with the Huntington’s disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington’s disease. Huntington’s disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be classified into stages based on thresholds of stage-specific landmark assessments.
  • a subject suffering from Huntington’s disease is HD-ISS Stage 3.
  • a subject susceptible to Huntington’s disease is HD-ISS Stage 0.
  • a subject is HD-ISS Stage 1.
  • a subject is HD-ISS Stage 2.
  • Treatment of HTT-Related Conditions, Disorders or Diseases the present disclosure provides a HTT oligonucleotide which targets HTT (e.g., a HTT oligonucleotide comprising a HTT target sequence or a sequence complementary to a HTT target sequence) and directs target-specific knockdown of HTT, including, for example, WVE-003.
  • HTT e.g., a HTT oligonucleotide comprising a HTT target sequence or a sequence complementary to a HTT target sequence
  • WVE-003 is administered intrathecally in an amount of about 30, about 60, about 90, about 120, about 150 or about 168 mg, and is administered as a liquid formulation (including, but not limited to, a solution in water, or an aCSF solution, or a solution in aCSF reconstituted from a lyophilized preparation or a solution in sodium chloride, or a solution in sodium chloride reconstituted from a lyophilized preparation).
  • the present disclosure provides a HTT oligonucleotide which directs target-specific knockdown of HTT mediated by RNase H and/or RNA interference.
  • the present disclosure provides methods for preventing and/or treating HTT- related conditions, disorders or diseases using provided HTT oligonucleotides and compositions thereof.
  • a HTT-related condition is Huntington’s disease, and/or one or more symptoms of Huntington’s disease.
  • the present disclosure provides oligonucleotides and compositions thereof for use as medicaments, e.g., for HTT-related conditions, disorders or diseases.
  • the present disclosure provides oligonucleotides and compositions thereof for use in the treatment of HTT-related conditions, disorders or diseases.
  • the present disclosure provides oligonucleotides and compositions thereof for the manufacture of medicaments for the treatment of HTT-related conditions, disorders or diseases.
  • the present disclosure provides a method for preventing, treating or ameliorating a HTT-related condition, disorder or disease in a subject susceptible thereto or suffering therefrom, comprising administering to the subject a therapeutically effective amount of a HTT oligonucleotide or a pharmaceutical composition thereof.
  • the present disclosure provides a method for treating or ameliorating a HTT- related condition, disorder or disease in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a HTT oligonucleotide or a pharmaceutical composition thereof.
  • a HTT oligonucleotide is WVE-003.
  • a therapeutically effective amount is about 30, about 60, about 90, about 120, about 150 or about 168 mg.
  • a HTT-related condition, disorder or disease is Huntington’s disease (HD), also known as Huntington’s Chorea.
  • HD Huntington’s disease
  • a HTT-related condition, disorder or disease is: juvenile HD, akinetic-rigid, or Westphal variant HD.
  • the present disclosure provides a method for reducing HTT gene expression in a cell, comprising: contacting the cell with a HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for reducing the level of a HTT transcript in a cell, comprising: contacting the cell with a HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for reducing the level of a HTT protein in a cell, comprising: contacting the cell with a HTT oligonucleotide or a composition thereof.
  • provided methods selectively reduce levels of HTT transcripts and/or products encoded thereby that are related to conditions, disorders or diseases.
  • HTT is expressed in all cells, with the highest concentrations are found in the brain and testes, with moderate amounts in the liver, heart, and lungs.
  • a cell is in brain, testes, liver, heart, or lungs.
  • the present disclosure provides a method for decreasing HTT gene expression in a mammal in need thereof, comprising administering to the mammal a nucleic acid-lipid particle comprising a provided HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for in vivo delivery of a HTT oligonucleotide, comprising administering to a mammal a HTT oligonucleotide or a composition thereof.
  • a mammal is a human.
  • a mammal is afflicted with, suffering from and/or susceptible to a HTT-related condition, disorder or disease.
  • a subject or subject suitable for treatment of a HTT-related condition, disorder or disease can be identified or diagnosed by a health care professional.
  • a health care professional For example, for a neurological condition, disorder or disease, a physical exam may be followed by a thorough neurological exam.
  • an neurological exam may assess motor and sensory skills, nerve function, hearing and speech, vision, coordination and balance, mental status, and/or changes in mood or behavior.
  • Example symptoms of neurological conditions, disorders or diseases, such as Huntington’s disease (HD) include weakness in the arms, legs, feet, or ankles; slurring of speech; difficulty lifting the front part of the foot and toes; hand weakness or clumsiness; muscle paralysis; rigid muscles; involuntary jerking or writing movements (chorea); involuntary, sustained contracture of muscles (dystonia); bradykinesia; loss of automatic movements; impaired posture and balance; lack of flexibility; tingling parts in the body; electric 53 of 265 12842751v1 Attorney Docket No.: 2010581-1510 shock sensations that occur with movement of the head; twitching in arm, shoulders, and tongue; difficulty swallowing; difficulty breathing; difficulty chewing; partial or complete loss of vision; double vision; slow or abnormal eye movements; tremor; unsteady gait; fatigue; loss of memory; dizziness; difficulty thinking or concentrating; difficulty reading or writing; misinterpretation of spatial relationships; disorientation; depression; anxiety; difficulty making
  • a symptom of Huntington’s disease is any of: insoluble protein accumulation; huntingtin protein aggregate accumulation; neuronal aggregates in the striatum; alteration in the size and number of neuronal intranuclear inclusions and other markers of HD; alteration in regulation of DARPP-32 expression; striatal atrophy; striatal and cortical neurodegeneration; alteration of blood glucose and/or insulin levels; or neuronal loss and gliosis, particularly in the cortex and striatum.
  • a symptom of Huntington’s disease is any of: behavioral and neuropathological abnormalities; in test animals, altered rotarod performance; reduction of weight loss; alteration of lifespan; behavioral disturbance; emotional, motor and cognitive alterations or impairment; depression; irritability; involuntary movements (chorea); choreiform movements; impaired coordination; excessive spontaneous movements which are irregularly timed, randomly distributed and abrupt; bradykinesia; dystonia; seizures; rigidity; ocularmotor dysfunction; tremor; fine motor incoordination; dysarthria; dysphagia; subcortical dementia; progressive dementia; or psychiatric disturbance.
  • a provided oligonucleotide or a composition thereof prevents, treats, ameliorates, or slows progression of a HTT-related condition, disorder or disease, or at least one symptom of a HTT-related condition, disorder or disease. In some embodiments, a provided oligonucleotide or a composition thereof prevents, treats, ameliorates, or slows progression of a HTT-related condition, disorder or disease, or two or more symptoms of a HTT-related condition, disorder or disease.
  • a method of the present disclosure is for the treatment of Huntington’s disease in a subject wherein the method comprises administering to a subject a therapeutically effective amount of a HTT oligonucleotide or a pharmaceutical composition thereof.
  • the HTT oligonucleotide is WVE-003.
  • a subject has an allele or transcript that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE-003.
  • HTT transcripts 54 of 265 12842751v1 Attorney Docket No.: 2010581-1510 comprising an expanded CAG repeat region are fully complementary to the base sequence of WVE-003.
  • a subject has an allele that does not contain an expanded CAG repeat region and is fully complementary to the base sequence of WVE-003. In some embodiments, a subject has a HTT allele that does not contain an expanded CAG repeat region and is not complementary to the base sequence of WVE-003 at rs362273. In some embodiments, HTT transcripts that do not contain an expanded CAG repeat region are not fully complementary to the base sequence of WVE-003 at rs362273. [0280] In some embodiments, a provided method reduces at least one symptom of Huntington’s disease wherein the method comprises administering to a subject a therapeutically effective amount of a HTT oligonucleotide or a pharmaceutical composition thereof.
  • the present disclosure provides a method for treating and/or ameliorating one or more symptoms associated with a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for reducing susceptibility to a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for preventing or delaying the onset of a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a HTT oligonucleotide or a composition thereof.
  • the present disclosure provides a method for treating and/or ameliorating one or more symptoms associated with a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a HTT oligonucleotide.
  • the present disclosure provides a method for reducing susceptibility to a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a HTT oligonucleotide.
  • the present disclosure provides a method for preventing or delaying the onset of a HTT-related condition, disorder or disease in a mammal in need thereof, the method comprising: administering to the mammal a therapeutically effective amount of a nucleic acid-lipid particle comprising a HTT oligonucleotide.
  • a mammal is a human.
  • a mammal is afflicted with and/or suffering from and/or susceptible to a HTT-related condition, disorder or disease.
  • a HTT oligonucleotide is WVE-003.
  • a therapeutically effective amount is about 30, about 60, about 90, about 120, about 150 or about 168 mg.
  • the present disclosure pertains to compositions and methods related to specific doses of WVE-003 (or a salt form thereof) which are about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, or about 168 mg.
  • about 30 mg is 30 mg +5%
  • about 60 mg is 60 mg +5%
  • about 90 mg is 90 55 of 265 12842751v1 Attorney Docket No.: 2010581-1510 mg +5%
  • about 120 mg is 120 mg +5%
  • about 150 mg is 150 mg +5% and/or about 168 mg is 168 mg +5%.
  • about 30 mg is 30 mg +10%
  • about 60 mg is 60 mg +10%
  • about 90 mg is 90 mg +10%
  • about 120 mg is 120 mg +10%
  • about 150 mg is 150 mg +10% and/or about 168 mg is 168 mg +10%.
  • about 30 mg is 30 mg +15%, about 60 mg is 60 mg +15%, about 90 mg is 90 mg +15%, about 120 mg is 120 mg +15%, about 150 mg is 150 mg +15% and/or about 168 mg is 168 mg +15%.
  • about 30 mg is 30 mg +20%, about 60 mg is 60 mg +20%, about 90 mg is 90 mg +20%, about 120 mg is 120 mg +20%, about 150 mg is 150 mg +20% and/or about 168 mg is 168 mg +20%.
  • about 30 mg is 30 mg +25%, about 60 mg is 60 mg +25%, about 90 mg is 90 mg +25%, about 120 mg is 120 mg +25%, about 150 mg is 150 mg +25% and/or about 168 mg is 168 mg +25%.
  • about 30 mg is 30 mg+30%, about 60 mg is 60 mg +30%, about 90 mg is 90 mg +30%, about 120 mg is 120 mg +30%, about 150 mg is 150 mg +30% and/or about 168 mg is 168 mg +30%.
  • about 30 includes but is not limited to: 25.6, 25.7, 25.8, 25.9, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9,32, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6,
  • about 30 includes but is not limited to: 24, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25, 25.1, 25.2, 25.3, 25.4, 25.5,25.6, 25.7, 25.8, 25.9, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9,32, 32.1,
  • about 30 includes but is not limited to: 24, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25, 25.1, 25.2, 25.3, 25.4, 25.5,25.6, 25.7, 25.8, 25.9, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 56 of 265 12842751v1 Attorney Docket No.: 2010581-1510 28.7, 28.8, 28.9, 29, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31, 31.1, 31.2, 31.3, 3
  • the present disclosure pertains to compositions and methods related to specific dose of WVE-003 (or a salt form thereof) which are about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, or about 168 mg.
  • the present disclosure pertains to compositions and methods related to specific doses of WVE-003 (or a salt form thereof) which are about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, or about 168mg, wherein the total amount of oligonucleotide in the dose is about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, or about 168 mg, respectively, and substantially all of the oligonucleotide in the dose is WVE-003.
  • the present disclosure provides WVE-003 preparations of high purity. Various technologies are available for assess WVE-003 purity. In some embodiments, purity is assessed using Protocol A as described herein.
  • impurities include n-x deletion sequences; n-1 deletion sequences and phosphodiesters; modified full length sequences and/or n+x addition sequences. Without wishing to be bound by any particular theory, this disclosure notes that at least some of the impurities will have at least some activity (e.g., capability to mediate allele-specific knockdown of a mutant HTT gene or gene product).
  • WVE-003 is administered to a subject at a dose of about 30, about 60, about 90, about 120, about 150 or about 168 mg. In some embodiments, multiple doses of WVE-003 are administered to a subject. In some embodiments, multiple doses of WVE-003 are administered to a subject at regular intervals.
  • multiple doses of WVE-003 are administered to a subject approximately monthly (e.g., with an interval of about 1 month between dosages). In some embodiments, multiple doses of WVE-003 are administered to a subject approximately once every 2 months (e.g., with an interval of about 2 months between dosages). In some embodiments, multiple doses of WVE-003 are administered to a subject approximately once approximately every 8 weeks (e.g., with an interval of about 8 weeks between dosages). In some embodiments, multiple doses of WVE-003 are administered to a subject approximately once approximately every 12 weeks (e.g., with an interval of about 12 weeks between dosages).
  • each of the multiple doses is about the same, e.g., about 30 mg. 57 of 265 12842751v1 Attorney Docket No.: 2010581-1510 [0296]
  • multiple doses of WVE-003 are administered to a subject once approximately every 4 weeks (e.g., with an interval of approximately 4 weeks between dosages).
  • multiple doses of WVE-003 are administered to a subject once approximately every 8 weeks (e.g., with an interval of approximately 8 weeks between dosages).
  • multiple doses of WVE-003 are administered to a subject once approximately every 12 weeks (e.g., with an interval of approximately 12 weeks between dosages).
  • the subject is administered two or more doses of WVE-003, and the interval between any two of the doses is about a month or about 4 weeks. In some embodiments, the subject is administered two or more doses of WVE-003, and the interval between any two of the doses is about 2 months or about 8 weeks. In some embodiments, the subject is administered two or more doses of WVE-003, and the interval between any two of the doses is about 3 months or about 12 weeks. [0298] In some embodiments, the subject is administered two or more doses of WVE-003, approximately monthly or approximately once every 4 weeks. In some embodiments, the subject is administered two or more doses of WVE-003, approximately once every 2 months or approximately once every 8 weeks.
  • the subject is administered two or more doses of WVE-003, approximately once every 3 months or approximately once every 12 weeks. [0299] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 2 months. In some embodiments, the subject is administered WVE-003 approximately once every two months for at least about 2 months. [0300] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 4 months. In some embodiments, the subject is administered WVE-003 approximately once every two months for at least about 4 months. [0301] In some embodiments, the subject is administered WVE-003 approximately monthly for at least about 8 months. In some embodiments, the subject is administered WVE-003 approximately once every two months for at least about 8 months.
  • the subject is administered WVE-003 approximately once every 4 weeks for at least about 8 weeks. In some embodiments, the subject is administered WVE-003 approximately once every 8 weeks for at least about 16 weeks. [0303] In some embodiments, the subject is administered WVE-003 approximately once every 4 weeks for at least about 12 weeks. In some embodiments, the subject is administered WVE-003 approximately once every 12 weeks for at least about 12 weeks. [0304] In some embodiments, the subject is administered WVE-003 approximately once every 4 weeks for at least about 16 weeks. In some embodiments, the subject is administered WVE-003 approximately once every 8 weeks for at least about 16 weeks.
  • the subject is administered WVE-003 approximately once every 8 weeks for at least about 24 weeks. In some embodiments, the subject is administered WVE-003 approximately once 58 of 265 12842751v1 Attorney Docket No.: 2010581-1510 every 12 weeks for at least about 24 weeks. [0306] In some embodiments, administration of a HTT oligonucleotide to a subject or patient is capable of mediating any one or more of: slowing Huntington’s disease progression, delaying the onset of HD or at least one symptom thereof, improving one or more indicators of HD, and/or increasing the survival time or lifespan of the subject or patient.
  • slowing disease progression relates to the prevention of, or delay in, a clinically undesirable change in one or more clinical parameters in an individual and/or susceptible to HD, such as those described herein. It is well within the abilities of a physician to identify a slowing of disease progression in an individual suffering from HD, using one or more of the disease assessment tests described herein. Additionally, it is understood that a physician may administer to the individual diagnostic tests other than those described herein to assess the rate of disease progression in an individual suffering from HD. [0308] In some embodiments, delaying the onset of HD or a symptom thereof relates to delaying one or more undesirable changes in one or more indicators of HD that are negative for HD.
  • indicators of HD include parameters employed by a medical professional, such as a physician, to diagnose or measure the progression of HD, and include, without limitation, genetic testing, hearing, eye movements, strength, coordination, chorea (rapid, jerky, involuntary movements), sensation, reflexes, balance, movement, mental status, dementia, personality disorder, family history, weight loss, and degeneration of the caudate nucleus.
  • an improvement in an indicator of HD relates to the absence of an undesirable change, or the presence of a desirable change, in one or more indicators of HD.
  • an improvement in an indicator of HD is evidenced by the absence of a measurable change in one or more indicators of HD.
  • an improvement in an indicator of HD is evidenced by a desirable change in one or more indicators of HD.
  • a slowing of disease progression may further comprise an increase in survival time in an individual suffering from and/or susceptible to HD.
  • an increase in survival time relates to mean increasing the survival of an individual suffering from and/or susceptible to HD, relative to an approximate survival time based upon HD progression and/or family history of HD.
  • a physician can use one or more of the disease assessment tests described herein to predict an approximate survival time of an individual suffering from and/or susceptible to HD.
  • a physician may additionally use the family history of an individual suffering from and/or susceptible to HD or comparisons to other HD patients with similar genetic profile (e.g., number of CAG repeats) to predict expected survival time.
  • the present disclosure provides a method of inhibiting HTT expression in a 59 of 265 12842751v1 Attorney Docket No.: 2010581-1510 cell, the method comprising: (a) contacting the cell with a HTT oligonucleotide; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of a mRNA transcript of a HTT gene, thereby inhibiting expression of the HTT gene in the cell.
  • HTT expression is inhibited by at least 30%.
  • the present disclosure provides a method of treating a condition, disorder or disease mediated by HTT expression comprising administering to a human suffering therefrom a therapeutically effective amount of a HTT oligonucleotide or a composition thereof.
  • administration causes a decrease in the expression, activity and/or level of a HTT transcript.
  • administration is associated with a decrease in the expression, activity and/or level of a HTT transcript.
  • administration is followed by a decrease in the expression, activity and/or level of a HTT transcript.
  • the present disclosure provides a HTT oligonucleotide for use in a subject to treat a HTT-related condition, disorder or disease.
  • a HTT-related condition, disorder or disease is Huntington’s disease.
  • a provided method reduces amount and/or percentage of mHTT protein.
  • a provided method reduces amount and/or percentage of mHTT protein in CSF.
  • a provided method increases percentage of wtHTT protein.
  • a provided method increases percentage of wtHTT protein in CSF.
  • a provided method does not reduce amount of wtHTT protein, or does not reduce amount of wtHTT protein by more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, a provided method does not reduce amount of wtHTT protein, or does not reduce amount of wtHTT protein by more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in CSF.
  • amount and/or percentage of mHTT, wtHTT and/or total HTT are independently assessed after a suitable period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months) after one or more doses each independently as described herein.
  • a suitable period of time e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months
  • a subject is administered an oligonucleotide, e.g., a HTT oligonucleotide (e.g., WVE-003), or a salt form thereof, or a composition thereof and an additional agent and/or method, e.g., an additional therapeutic agent and/or method.
  • an oligonucleotide or composition thereof can be administered alone or in combination with one or more additional therapeutic agents and/or treatment.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • provided oligonucleotides and additional therapeutic components are administered concurrently. In some embodiments, provided oligonucleotides and additional therapeutic components are administered as one composition. In some embodiments, at a time point a subject being administered is exposed to both 60 of 265 12842751v1 Attorney Docket No.: 2010581-1510 provided oligonucleotides and additional components at the same time. Allele-specific knockdown of a mutant HTT transcript as a Treatment for Huntington’s disease [0317] In some embodiments, a treatment for Huntington’s disease comprises the use of a HTT oligonucleotide which is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • the present disclosure provides methods for treatment of Huntington’s disease comprising the step of administering to a subject suffering therefrom or susceptible thereto a HTT oligonucleotide, or a composition comprising a HTT oligonucleotide.
  • the present disclosure demonstrates that chirally controlled oligonucleotide/chirally controlled oligonucleotide compositions are unexpectedly effective for modulating allele-specific knockdown of a mutant HTT transcript compared to otherwise identical but non-chirally controlled oligonucleotide/oligonucleotide compositions.
  • the term chirally controlled can be equated with stereopure or stereodefined.
  • a composition comprising a HTT oligonucleotide is useful for treatment of a Huntingtin-related disorder of the central nervous system.
  • the present disclosure provides a method of treatment of a Huntingtin-related disorder of the central nervous system, wherein the method comprises the step of administering a therapeutically effective amount of a HTT oligonucleotide to a subject suffering from a Huntingtin-related disorder of the central nervous system.
  • a HTT oligonucleotide is administered outside the central nervous system (as non-limiting examples, intrathecally or intramuscularly) to a subject suffering from and/or susceptible to a Huntingtin-related disorder of the central nervous system, and the HTT oligonucleotide is capable of passing through the blood-brain barrier into the central nervous system.
  • a HTT oligonucleotide is administered directly into the central nervous system (as non-limiting example, via intrathecal, intraventricular, intracranial, etc., delivery).
  • a HTT gene or transcript has a CAG repeat expansion.
  • a HTT subject has a CAG repeat expansion.
  • allele-specific knockdown of a mutant HTT transcript can be employed to remove or reduce effects of such a mutation by decreasing the level, expression and/or activity of a protein expressed from a mHTT transcript.
  • a HTT subject or a subject suspected to have HTT is analyzed for HTT genotype prior to administration of a composition comprising a HTT oligonucleotide.
  • a HTT subject or a subject suspected to have HTT is analyzed for HTT 61 of 265 12842751v1 Attorney Docket No.: 2010581-1510 phenotype prior to administration of a composition comprising a HTT oligonucleotide.
  • a HTT subject is analyzed for genotype and phenotype to determine the relationship of HTT genotype and HTT phenotype prior to administration of a composition comprising a HTT oligonucleotide.
  • a subject is genetically verified to have Huntington’s disease prior to administration of a composition comprising a HTT oligonucleotide.
  • analysis of HTT genotype or genetic verification of mHTT in a subject comprises determining if the subject has one or more deleterious mutations in HTT. [0327] In some embodiments, analysis of HTT genotype or genetic verification of mHTT in a subject comprises determining if the subject has, on the same chromosome, a CAG repeat expansion and a SNP targeted by a particular HTT oligonucleotide; in some embodiments, such an analysis is referenced as phasing.
  • a target nucleic acid sequence and a reference nucleic acid sequence differs at one or more sites, e.g., a mutation site, a single-nucleotide polymorphism (SNP) site, etc.
  • a target nucleic acid sequence and a reference nucleic acid sequence comprise a difference at a SNP site.
  • a site in a target nucleic acid is fully complementary to a site in an oligonucleotide of the present disclosure while the corresponding site in a reference nucleic acid is not.
  • analysis of HTT genotype or genetic verification of mHTT informs the selection of a composition comprising a HTT oligonucleotide useful for treatment.
  • an abnormal or mutant HTT gene or a portion thereof is removed or copied from a subject or a subject’s cell(s) or tissue(s) and the abnormal or mutant HTT gene, or a portion thereof comprising the abnormality or mutation, or a copy thereof, is inserted into a cell.
  • this cell can be used to test various compositions comprising a HTT oligonucleotide to predict if such a composition would be useful as a treatment for the subject.
  • the cell is a myoblast or myotubule.
  • phasing is performed on the subject’s genome to determine if the CAG repeat expansion is on the same chromosome as a SNP targeted by a HTT oligonucleotide capable of mediating allele-specific knockdown.
  • a HTT oligonucleotide capable of mediating allele-specific knockdown of a mutant HTT gene or gene product thereof, and useful for methods of treatment of Huntington’s disease is WVE-003.
  • Chirally Controlled HTT Oligonucleotides and Compositions Thereof [0333] Among other things, the present disclosure pertains to chirally controlled HTT oligonucleotides and oligonucleotides, e.g., WVE-003, and methods thereof.
  • stereorandom HTT oligonucleotide preparations contain a plurality of distinct chemical entities that differ from one another, e.g., in the stereochemical structure of 62 of 265 12842751v1 Attorney Docket No.: 2010581-1510 individual backbone chiral centers within the HTT oligonucleotide chain.
  • a stereorandom HTT oligonucleotide preparation e.g., a random mixture of diastereoisomers
  • these stereoisomers may have the same base sequence and/or chemical modifications, they are different chemical entities at least about due to their different backbone stereochemistry, and they can have different properties, e.g., activities, toxicities, distribution etc.
  • the present disclosure provides chirally controlled compositions that are or contain particular stereoisomers of HTT oligonucleotides of interest (e.g., WVE-003); in contrast to chirally uncontrolled compositions, chirally controlled compositions comprise controlled levels of particular stereoisomers of HTT oligonucleotides.
  • level of a particular stereoisomer, e.g., WVE-003, of a chirally controlled oligonucleotide composition is enriched as described herein (e.g., in some embodiments, each chiral internucleotidic linkage independently has a stereopurity of about 97%, 98%, 99% or more).
  • a particular stereoisomer may be defined, for example, by its base sequence, its pattern of backbone linkages, its pattern of backbone chiral centers, and pattern of backbone phosphorus modifications, etc.
  • base sequence may refer solely to the sequence of bases and/or to the identity and/or modification status of nucleoside residues (e.g., of sugar and/or base components, relative to standard naturally occurring nucleotides such as adenine, cytosine, guanosine, thymine, and uracil) in a HTT oligonucleotide and/or to the hybridization character (i.e., the ability to hybridize with particular complementary residues) of such residues.
  • nucleoside residues e.g., of sugar and/or base components, relative to standard naturally occurring nucleotides such as adenine, cytosine, guanosine, thymine, and uracil
  • the present disclosure demonstrates that property improvements (e.g., improved activities, lower toxicities, etc.) achieved through inclusion and/or location of particular chiral structures within a HTT oligonucleotide can be comparable to, or even better than those achieved through use of chemical modifications, e.g., particular backbone linkages, residue modifications, etc. (e.g., through use of certain types of modified phosphates [e.g., phosphorothioate, substituted phosphorothioate, etc.], sugar modifications [e.g., 2’- modifications, etc.], and/or base modifications [e.g., methylation, etc.]).
  • chemical modifications e.g., particular backbone linkages, residue modifications, etc.
  • residue modifications e.g., through use of certain types of modified phosphates [e.g., phosphorothioate, substituted phosphorothioate, etc.], sugar modifications [e.g., 2’- modifications, etc.], and/or base modifications [
  • the present disclosure demonstrates that chirally controlled HTT oligonucleotide compositions of HTT oligonucleotides (e.g., WVE-003, including various salt forms thereof) demonstrate unexpectedly high capability for mediating allele-specific knockdown of a mutant HTT transcript, and are useful for treatment and/or prevention of Huntington’s disease.
  • a composition of WVE-003 is a chirally controlled oligonucleotide composition capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • a chirally controlled WVE-003 composition is utilized to target human Huntingtin pre-messenger ribonucleic acid (mRNA) in order to induce allele-specific knockdown of a mutant HTT transcript and Huntingtin protein restoration in subjects with Huntington’s disease (HTT).
  • WVE-003 comprises a base sequence that can be antisense to and hybridize by complementary base pairing to a HTT transcript.
  • WVE-003 are developed and manufactured using certain such technologies. [0338] In some embodiments, WVE-003 is utilized to target human Huntingtin (HTT) pre-messenger ribonucleic acid (mRNA) in order to induce allele-specific knockdown of a mutant HTT transcript in subjects with Huntington’s disease (HTT).
  • HTT human Huntingtin
  • mRNA pre-messenger ribonucleic acid
  • an oligonucleotide composition comprises WVE-003.
  • an oligonucleotide composition is a chirally controlled oligonucleotide composition of WVE- 003.
  • such a composition is a pharmaceutical composition of WVE-003.
  • an oligonucleotide e.g., WVE-003, may be administered in one or more forms (e.g., acid forms, various salt forms, etc.).
  • a form is an acid form.
  • a form is a salt form.
  • a form is a sodium salt form.
  • an oligonucleotide, e.g., WVE-003, is administered as a salt form, e.g., a sodium salt form, optionally in a solution.
  • a composition e.g., a pharmaceutical composition, a chirally controlled oligonucleotide composition, etc., comprises one or more forms of WVE-003.
  • an amount of an oligonucleotide e.g., an amount of an oligonucleotide being administered, is the corresponding amount in a particularly form (e.g., an acid form) of all forms, e.g., all forms being administered (e.g., one or more salt forms (e.g., sodium salt form).
  • a particularly form e.g., an acid form
  • all forms being administered e.g., one or more salt forms (e.g., sodium salt form).
  • multiple forms of an oligonucleotide may exist in a composition.
  • compositions comprising WVE-003 are each a chirally pure or chirally controlled oligonucleotide composition of WVE-003.
  • chirally controlled oligonucleotide compositions are typically prepared through chirally controlled oligonucleotide preparation to stereoselectively form one or more chiral internucleotidic linkages (e.g., using chiral auxiliaries as exemplified in the present disclosure, compared to non-chirally controlled (stereorandom, non-stereoselective, racemic) oligonucleotide synthesis such as traditional phosphoramidite-based oligonucleotide synthesis using no chiral auxiliaries or chiral catalysts to purposefully control stereoselectivity).
  • a chirally controlled oligonucleotide composition of an oligonucleotide is enriched, relative to a substantially racemic preparation of oligonucleotides having the same base sequence and the same modifications, for the particular oligonucleotide (e.g., for chirally controlled oligonucleotide compositions of WVE-003, enriched for WVE-003).
  • such enrichment can be characterized in that compared to a substantially racemic preparation, at each chirally controlled internucleotidic linkage, a higher level of the linkage phosphorus has the desired configuration.
  • each chirally controlled internucleotidic linkage independently has a diastereopurity of at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with respect to its chiral linkage phosphorus.
  • a diastereopurity is at least 95%.
  • a diastereopurity is at least 96%.
  • a diastereopurity is at least 97%.
  • a diastereopurity is at least 98%.
  • a diastereopurity is about 99% or more.
  • a preparation typically comprises an oligonucleotide, e.g., WVE-003, and one or more other oligonucleotides and/or other impurities, as manufacturing processes rarely can reach 100% selectivity and/or purity (including but not limited to diastereomeric purity).
  • WVE-003 oligonucleotide
  • other oligonucleotides and/or other impurities can and are properly controlled.
  • a chirally controlled oligonucleotide composition can consist essentially of a desired oligonucleotide (e.g., WVE-003), e.g., the other oligonucleotides being impurities from manufacturing of that oligonucleotide.
  • impurities include oligonucleotides which are similar but different than the desired oligonucleotide (e.g., one or more internucleotidic linkage in the impurity may have an undesired configuration; and/or the impurity can be shorter or longer than the desired oligonucleotide).
  • a purity e.g., a purity level, for example of WVE-003 is about or at least about 75%. In some embodiments, a purity is about or at least about 80%. In some embodiments, a purity is about or at least about 81%.
  • a purity is about or at least about 82%. In some embodiments, a purity is about or at least about 83%. In some embodiments, a purity is about or at least about 84%. In some embodiments, a purity is about or at least about 85%. In some embodiments, a purity is about or at least about 86%. In some embodiments, a purity is about or at least about 87%. In some embodiments, a purity is about or at least about 88%. In some embodiments, a purity is about or at least about 89%. In some embodiments, a purity is about or at least about 90%. In some embodiments, a purity is about or at least about 91%. In some embodiments, a purity is about or at least about 92%.
  • a purity is about or at least about 93%. In some embodiments, a purity is about or at least about 94%. In some embodiments, a purity is about or at least about 95%. In some embodiments, a purity is about or at least about 96%. In some embodiments, a purity is about or at least about 97%. In some embodiments, a purity is about or at least about 98%. In some embodiments, a purity is about or at least about 99%. [0347] In some embodiments, purity of WVE-003 in a preparation, composition, medicament, etc., can be determined using various suitable methods as described herein.
  • purity is assessed using chromatography with UV detection, e.g., UPLC-UV as described in, and purity is measured as peak area% at a given wavelength, e.g., 260 nm.
  • a purity is assessed as described in Protocol A.
  • a purity is assessed as described in Protocol B.
  • a purity is assessed by dimer modeling.
  • the present disclosure provides technologies for manufacturing an oligonucleotide, e.g., WVE-003 , that are particularly useful for stereoselective large scales preparations.
  • a preparation of WVE-003, e.g. WVE-003 drug substance or drug product is a solid. In some embodiments, it is in a white to off-white powder.
  • solubility of prepared WVE- 003 in water was determined to be at least 79.20 mg/ mL as determined by UV spectrophotometry (e.g., at 260 nm).
  • pH of WVE-003 preparations in purified water is from 6.0-8.0. Unless noted otherwise, extinction coefficient of 181181 M -1 cm -1 is utilized herein, e.g., to calculate WVE-003 concentrations/amounts from UV at 260 nm.
  • an oligonucleotide e.g., WVE-003
  • WVE-003 is chemically synthesized using commercially available synthesizers in compliance with appropriate cGMP regulations.
  • Manufacture of WVE-003, e.g., drug substance is a multi-step process that includes solid-phase oligonucleotide synthesis, cleavage of the crude protected oligonucleotide from the solid support, removal of protecting groups (deprotection), preparative anion exchange (AEX) chromatographic purification, concentration and desalting, filtration, lyophilization and packaging.
  • a flow diagram depicting the WVE-003 drug substance manufacturing process is shown in Figure 1.
  • stereochemistry of an oligonucleotide is established through control of the starting materials for synthesis as well as the synthetic process.
  • phosphoramidites prepared from the chiral auxiliaries (L)-DPSE, (D)-DPSE and (L)-PSM during the coupling step ensures that the intended stereodefined Sp phosphorothioate diester, Rp phosphorothioate diester and Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester linkages, respectively, are obtained.
  • the present disclosure provides methods for manufacturing various drug products as described herein.
  • the present disclosure provides products (e.g., crude/purified oligonucleotides from stereoselective preparation, crude compositions, purified compositions, formulated compositions, pharmaceutical compositions, drug substances, drug products, etc.) by provided processes.
  • provided products are of certain purities as described herein.
  • provided products are suitable for therapeutic uses as described herein.
  • provided products achieve one or more properties and/or activities as described herein.
  • preparation of WVE-003 comprises multiple cycles (e.g., as described below).
  • 66 of 265 12842751v1 Attorney Docket No.: 2010581-1510
  • each cycle to introduce a stereodefined phosphorothioate or stereodefined phosphoramidate consists of 5’-detritylation, coupling, capping of exposed chiral auxiliary secondary amine (Capping-1), thiolation or imidation, respectively, and capping of unreacted 5’-hydroxyl groups (Capping-2)
  • each cycle to introduce a phosphodiester consists of 5’-detritylation, coupling, oxidation, and Capping-2, and each coupling reaction is carried out by activation of the appropriate phosphoramidite and reaction with the free 5’-hydroxyl group of a support-immobilized protected nucleoside or oligonucleotide.
  • the (L)-PSM chiral auxiliary and cyanoethyl phosphate protecting groups are removed from the crude oligonucleotide by on-column treatment with diethylamine (DEA) in acetonitrile (ACN), and the (L) and (D) DPSE chiral auxiliaries are removed by treatment with TEA .
  • DEA diethylamine
  • ACN acetonitrile
  • DPSE chiral auxiliaries are removed by treatment with TEA .
  • HF triethylamine hydrofluoride
  • the resulting crude oligonucleotide is purified using anion exchange (AEX) chromatography, and the purified oligonucleotide is concentrated and desalted by tangential flow filtration, followed by filtration, lyophilization and packaging to yield the WVE-003 drug substance.
  • AEX anion exchange
  • Certain steps to manufacture WVE-003 drug substance are described in further detail below as examples. Certain key functional groups are described below.
  • the present disclosure provides WVE-003, and preparations and compositions thereof. In some embodiments, the present disclosure provides technologies for manufacturing WVE-003. In some embodiments, the present disclosure provides technologies for assessing and/or characterizing WVE-003.
  • the present disclosure provide technologies for assessing purity of WVE-003, e.g., Protocol A.
  • the present disclosure provide technologies for confirming stereochemical identity of WVE-003 (or a stereoisomer thereof (e.g., with respect to chiral linkage phosphorus)), e.g., using IP-RP-UPLC (e.g., according to Protocol B).
  • the present disclosure provide technologies for assessing stereopurity of WVE-003, e.g., using IP-RP-UPLC (e.g., according to Protocol B), dimer modeling, etc.
  • the present disclosure provides methods for using WVE-003.
  • the present disclosure provides methods for treating Huntington’s disease, comprising administering to a subject suffering therefrom an amount of WVE-003 as described herein.
  • a therapeutic uses of oligonucleotides include modulating the function of target mHTT RNAs to reduce the production of disease-associated mHTT proteins.
  • the mechanism of action used by many oligonucleotides, including antisense oligonucleotides, is to promote degradation of the target mHTT RNA.
  • modifications of phosphodiester linkages e.g., use of phosphorothioate linkages, improve the stability, biodistribution, and cellular uptake of oligonucleotides.
  • the use of chiral internucleotidic linkages in oligonucleotide synthesis can create a chiral center at the linkage phosphorus.
  • a chiral linkage phosphorus center can have either an “Sp” or “Rp” configuration.
  • a conventional stereorandom preparation of an oligonucleotide that contains n chiral linkage phosphorus is a mixture of 2 n stereoisomers with respect to chiral linkage phosphorus centers, each of which stereoisomers share the same constitution but differs in stereochemistry along its backbone.
  • a stereorandom preparation can have over 131,000 (2 17 ) stereoisomers with respect to chiral linkage phosphorus, each of which stereoisomers exists at a very low level ( ⁇ 1/131000).
  • WVE-003 utilized herein are prepared stereoselectively.
  • each chiral internucleotidic linkage is independently formed with about 97% or more diastereoselectivity (e.g., as measured through preparation of a suitable dimer). In some embodiments, most chiral internucleotidic linkages are independently formed with about 98% or more diastereoselectivity. In some embodiments, one or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more chiral internucleotidic linkages are independently formed with about 99% or more diastereoselectivity.
  • overall diastereoselectivity is about 80% or more. In some embodiments, it is about 81% or more. In some embodiments, it is about 82% or more. In some embodiments, it is about 83% or more. In some embodiments, it is about 84% or more. In some embodiments, it is about 85% or more.
  • an oligonucleotide is WVE-003 which is a stereodefined oligonucleotide 71 of 265 12842751v1 Attorney Docket No.: 2010581-1510 that can selectively target mHTT, leaving wtHTT relatively unaffected.
  • WVE-003 can specifically targets the mHTT mRNA transcript, at the A variant of SNP rs362273 (SNP3).
  • SNP3 is a single variation that in some instances can be associated with a mutated gene.
  • SNP3 One of the most frequent SNPs in the mHTT gene is SNP3, which has been reported to be present in approximately 40% to 45% of patients with HD. Kay C et al. Clin Genet.
  • WVE-003 is utilized as a disease-modifying agent for the treatment of subjects with Huntington’s disease (HD).
  • WVE-003 is a stereopure antisense oligonucleotide (ASO) utilized to selectively target the mutant form of the huntingtin (mHTT) gene transcript.
  • ASO stereopure antisense oligonucleotide
  • a HTT oligonucleotide, or a salt form thereof is WVE-003 or a salt form thereof.
  • an oligonucleotide composition comprises WVE-003 or a salt form thereof.
  • the base sequence of WVE-003 is 5'-GUUGATCTGTAGCAGCAGCT -3'.
  • WVE-003 may be described as: 5'- mG*SmUn001RmUmGn001RmA*ST*SC*ST*SG*ST*RA*SG*SC*SA*SG*Rm5Ceon001RAeoGeon001R m5Ceo*STeo -3', wherein: *S represents a Sp phosphorothioate linkage; *R represents a Rp phosphorothioate linkage; mX represents 2’-O-methylribonucleoside; X represents 2’-deoxyribonucleoside; Xeo represents 2’-O-(2-methoxyethyl)ribonucleoside; m5Ceo represents 2’-O-(2-methoxyethyl)-5-methylcytidine; n001R represents Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester linkage (PN);
  • WVE-003 is in the form of a sodium salt.
  • a sodium salt of WVE-003 may be described as: [P(S)]-2′-O-methyl-P-thioguanylyl-(3′ ⁇ 5′)-[P(R)]-2′-O-methyl-P-deoxy-P-[(1,3-dimethylimidazolidin-2- ylidene)amino]uridylyl-(3′ ⁇ 5′)-2′-O-methyluridylyl-(3′ ⁇ 5′)-[P(R)]-2′-O-methyl-P-deoxy-P-[(1,3- dimethylimidazolidin-2-ylidene)amino]guanylyl-(3′ ⁇ 5′)-[P(S)]-2′-O-methyl-P-thioadenylyl-(3′ ⁇ 5′)-[P(S)]- P-thiothymidyly
  • a structure of a WVE-003 sodium salt is presented as below: As appreciated by those skilled in the art, in an acid form, each of Na + is replaced with H + . The zig-zag lines represent the linkage between oxygen at 3’ to the phosphorous in the internucleotide linkage.
  • This combination of internucleotide linkages can be illustrated with the following sequence of letters: 5′- SnROnRSSSSSRSSSSRnROnRS-3′, where ‘S’, ‘R’, “nR”, and ‘O’ represent Sp phosphorothioate diester, Rp phosphorothioate diester, Rp N-(1,3-dimethylimidazolidin-2-ylidene) phosphoramidate diester and phosphodiester linkages, respectively.
  • WVE-003 recognizes the disease-associated (e.g., mutant) allele of SNP rs362273 in the Huntingtin gene, is efficacious in reducing the level, expression and/or activity of a mHTT gene (or a gene product thereof), and is capable of mediating allele-specific knockdown of the mutant Huntingtin (mHTT) gene.
  • the efficacy and allele-specificity of chirally controlled WVE-003 composition is superior to that of various stereorandom oligonucleotide compositions.
  • HTT Oligonucleotides and HTT Oligonucleotide Compositions [0373]
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is chirally controlled.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is or comprises WVE-003.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of mHTT and is chirally controlled.
  • WVE- 003 is capable of mediating allele-specific knockdown of a mutant HTT transcript and a potential disease- modifying therapy for Huntington’s disease.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of mHTT and is chirally controlled.
  • the present disclosure provides methods of use of a HTT oligonucleotide or 74 of 265 12842751v1 Attorney Docket No.: 2010581-1510 a HTT oligonucleotide composition which is capable of mediating allele-specific knockdown of a HTT transcript of Huntingtin (HTT) (e.g., WVE-003).
  • HTT Huntingtin
  • the present disclosure provides compositions and methods for allele-specific knockdown of HTT transcripts, wherein allele-specific knockdown preferentially decreases the level, expression and/or activity of an allele(s) comprising Huntington’s disease-associated mutation.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is sufficient to mediate a clinically significant amount of allele- specific knockdown of a mutant HTT transcript in a subject.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is low enough to prevent or reduce the occurrence and/or reduce the severity of at least about one adverse event mediated by administration of the oligonucleotide or oligonucleotide composition (e.g. when administered at a higher dose) to the subject.
  • a therapeutically effective amount of a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is sufficient to mediate a clinically significant amount of allele-specific knockdown of a mutant HTT transcript in a subject, but is low enough to prevent or reduce the occurrence and/or reduce the severity of at least about one adverse event mediated by and/or associated with administration of the oligonucleotide or oligonucleotide composition (e.g. when administered at a higher dose) to the subject.
  • an adverse event is an adverse effect. In some embodiments, an adverse event is mild, moderate, severe, or serious.
  • a serious adverse event is more severe than an adverse event categorized as severe, moderate or mild.
  • a serious adverse event is immediately life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect not present at screening.
  • an adverse event can be treated with hydrocortisone and/or acetaminophen.
  • a severe adverse event is more severe than a moderate or mild adverse event.
  • a moderate adverse event is more severe than a mild adverse event.
  • an adverse event is: pyrexia, headache, vomiting, or tachycardia.
  • an adverse event is or is, is measured by, or is related to an increase in the inflammatory marker high-sensitivity C-reactive protein (hsCRP); an increase in complement factor Bb; or an increase in complement factor C3.
  • hsCRP high-sensitivity C-reactive protein
  • a HTT oligonucleotide or a HTT oligonucleotide composition is an oligonucleotide or oligonucleotide composition which targets a HTT transcript and is capable of modulating allele-specific knockdown of a mutant HTT transcript of the target transcript.
  • a HTT oligonucleotide or a HTT oligonucleotide composition is useful for preparation of a medicament for treatment of Huntington’s disease.
  • a HTT oligonucleotide or a HTT oligonucleotide composition is useful for treatment of Huntington’s disease.
  • a HTT oligonucleotide or a HTT oligonucleotide composition is useful for preparation of a medicament for treatment of Huntington’s disease, wherein the oligonucleotide is WVE-003, 75 of 265 12842751v1 Attorney Docket No.: 2010581-1510 and the medicament is administered in a dose equivalent to about 30, about 60, about 90, about 120, about 150 or about 168 mg WVE-003 free acid form.
  • the present disclosure provides methods of use of a HTT oligonucleotide or HTT oligonucleotide composition.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of mHTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is chirally controlled.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is or comprises WVE-003.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of mHTT and is chirally controlled.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of mHTT and is chirally controlled.
  • the present disclosure provides HTT oligonucleotide compositions and methods with reduced toxicity. In some embodiments, the present disclosure provides HTT oligonucleotide compositions and methods with reduced immune responses. In some embodiments, the present disclosure recognizes that various toxicities induced by HTT oligonucleotides are related to cytokine and/or complement activation. In some embodiments, the present disclosure provides HTT oligonucleotide compositions and methods with reduced or transient cytokine and/or complement activation. In some embodiments, the present disclosure provides HTT oligonucleotide compositions and methods with reduced complement activation via the alternative pathway.
  • Elongation of the growing oligonucleotide chain is achieved by reaction of the 5'-hydroxyl group of the support-bound oligonucleotide with an excess of a solution of the protected phosphoramidite, in the presence of an activator, either 5-(ethylthio)-1H-tetrazole (ETT) or 1-cyanomethyl imidazolium triflate salt (CMIMT) dissolved in acetonitrile.
  • ETT 5-(ethylthio)-1H-tetrazole
  • CMIMT 1-cyanomethyl imidazolium triflate salt
  • a solvent is a mixture of ethyl acetate and acetonitrile (e.g., about 50:50 v/v ethyl acetate:acetonitrile, about 20:80 v/v ethyl acetate:acetonitrile, etc.).
  • propylene carbonate can be utilized for preparing phosphoramidite solutions for oligonucleotide preparations, e.g., WVE-003 preparations.
  • propylene carbonate can be utilized to replace isobutyronitrile.
  • utilization of propylene carbonate reduces manufacturing cost and/or simplifies operations.
  • phosphoramidites are dissolved in propylene carbonate or a mixture thereof.
  • a solvent is propylene carbonate.
  • a solvent is a mixture of propylene carbonate and acetonitrile (e.g., about 50:50 v/v propylene carbonate:acetonitrile).
  • phosphoramidites are dissolved in acetonitrile, ethyl acetate, an ethyl acetate and acetonitrile mixture (e.g., about 20:80 v/v ethyl acetate:acetonitrile; about 50:50 v/v ethyl acetate:acetonitrile; etc.), or a propylene carbonate and acetonitrile mixture (e.g., about 50:50 v/v propylene carbonate:acetonitrile).
  • the phosphoramidite required in each coupling step is determined by the oligonucleotide sequence.
  • phosphoramidites and ETT activator are 77 of 265 12842751v1 Attorney Docket No.: 2010581-1510 used.
  • phosphoramidites and ETT activator are 77 of 265 12842751v1 Attorney Docket No.: 2010581-1510 used.
  • phosphoramidite/activator solutions are mixed inline, pushed onto the synthesis column, then recirculated through the column for appropriate amount of time. Subsequently, excess reagents are removed by flushing the synthesis column with acetonitrile.
  • capping reagents (1:1, v:v) (Capping Reagent A [Cap A]: N-methylimidazole / acetonitrile (20:80,v:v) and Cap B).
  • Capping Reagent A [Cap A]: N-methylimidazole / acetonitrile (20:80,v:v) and Cap B.
  • ‘capped’ 5'-O-acetylated support-bound oligonucleotide sequences are formed.
  • the excess capping reagents are washed from the column with acetonitrile.
  • Stage 2 - Cleavage and Deprotection [0393] Removal of phosphate protecting groups, (L)-PSM and (L)- and (D)-DPSE chiral auxiliaries from stereodefined phosphorimidate triester and phosphorothioate triester, cleavage of the crude oligonucleotide from the solid support, and removal of exocyclic nucleobase protecting groups is performed in a three-step process.
  • Step 1 (L)-PSM Chiral Auxiliary and Cyanoethyl Removal with Diethylamine Treatment
  • the crude oligonucleotide on the solid support is treated with a solution of diethylamine in ACN which simultaneously removes cyanoethyl protecting groups from the phosphate triester linkages, and (L)-PSM chiral auxiliary from the phosphorimidate triester to generate phosphodiester and phosphoramidate diester linkages, respectively.
  • Step 3 [0396] The crude oligonucleotide is then cleaved from the solid support by treatment with ammonium hydroxide in an appropriately sized pressure-rated vessel. This reaction effects the global deprotection of exocyclic amino groups (acetyl, benzoyl, and isobutyryl).
  • the purification is performed using sodium hydroxide buffered eluents.
  • a sodium chloride gradient is used to elute the oligonucleotide from the column.
  • the elution profile is monitored by ultraviolet (UV) 83 of 265 12842751v1 Attorney Docket No.: 2010581-1510 spectrophotometry.
  • Fractions are collected and neutralized with a sodium phosphate buffer. Mock pools are evaluated by IP-RP-UPLC. The pool containing oligonucleotide with the desired purity is subjected to the next step in the process.
  • Stage 4 Concentration and Desalting (Final UF/DF) [0399]
  • the selected fraction pool is then concentrated and diafiltered against purified water to remove the purification buffer by tangential flow filtration (TFF) using regenerated cellulose membrane cassettes.
  • the ultrafiltration/diafiltration (UF/DF) process proceeds as follows, the selected pool of fractions is pH neutralized with hydrochloric acid or sodium hydroxide and then concentrated.
  • the concentrated oligonucleotide is diafiltered against purified water, further concentrated and collected.
  • the system is flushed with purified water to maximize yield combining the concentrated desalted oligonucleotide with the rinses to give the final oligonucleotide solution.
  • Stage 5 Filtration, Lyophilization and Packaging
  • the oligonucleotide solution is filtered through a 0.2-micron filter and then placed in freeze drying tray(s) for lyophilization. After lyophilization, the final drug substance is isolated as a solid powder, which is packaged in sterile high-density polyethylene (HDPE) bottles, each of which is labeled and sealed in a Mylar foil pouch and stored at -20°C.
  • HDPE high-density polyethylene
  • Useful raw materials (solvents, reagents and auxiliary materials) used in the manufacture of WVE- 003, e.g., drug substance are listed below.
  • the starting materials used in the preparation of WVE-003 drug substance include 15 phosphoramidites, the Controlled Pore Glass (CPG) solid support and the 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADIH).
  • CPG Controlled Pore Glass
  • ADIH 2-azido-1,3-dimethylimidazolinium hexafluorophosphate
  • Reactive exocyclic groups on nucleobases are typically appropriately protected to render them unreactive during oligonucleotide synthesis, and the 5′-hydroxy functionality is protected as a 4,4′-dimethoxytrityl ether (DMTr).
  • DMTr 4,4′-dimethoxytrityl ether
  • WVE-003 starting materials are released based on a set of material specifications.
  • phosphoramidites have purity levels of about 85% or more, in many cases about 90% or more, in many cases about 95% or about 98% or more (RP-HPLC at about 260 nm (area %) and/or 31 P NMR by integration), about 97% or more P(III) purity (by 31 P NMR integration), and moisture content of less than about 0.4% or in many cases less than 0.2% (w/w).
  • Controlled Pore Glass 5′-ODMTr-2′-OMOE T solid support is a white to off white powder, 120-200 mesh particle size (analytical sieving), 540 - 600 ⁇ pore diameter (mercury intrusion), 0.20 – 0.24 g/cc density (tap density), ⁇ 0.8 cc/g pore volume (mercury intrusion), ⁇ 75 m 2 /g surface area (mercury intrusion) and 70 – 80 84 of 265 12842751v1 Attorney Docket No.: 2010581-1510 ⁇ mol/g in DMT ligand assay (spectrophotometric at 498 nm).
  • 2-Azido-1,3- dimethylimidazolinium hexafluorophosphate has a purity of about 98.0% or more (HPLC) and nitrogen content of about 23.70 – 24.80 % (elemental analysis).
  • WVE-003 has a level of purity of about 70%-90%, about 80%-90%, about 84%-90%, or about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% or more as determined by IP-RP-UPLC described herein.
  • Multiple lots of WVE-003 drug substance have been manufactured.
  • scale was over 20 mmol.
  • scale was multiple of about 20 mmol.
  • manufactured WVE-003 was utilized in clinical trials.
  • WVE-003 may be characterized by mass spectrometry.
  • mass spectrometry electrospray ionization mass spectrometry (ESI-MS) analysis was performed, and the theoretical average mass (free acid form) of WVE-003 is consistent with the experimentally determined value of 7257 Da.
  • the sequence of WVE-003 was confirmed by ESI-MS/MS sequencing. For example, in one assessment, at least one sequence-relevant fragment ion was observed for 19 nucleobases in the sequence within 5 ppm error of each calculated (expected) mass. The monoisotopic mass of the full-length oligonucleotide was also experimentally verified in the ESI-MS/MS analysis (7253.3428 Da), and the identities and locations of all 20 nucleobases have been demonstrated, confirming the sequence of WVE-003. [0411] Stereochemical identity is established through control of the starting materials for synthesis.
  • Synthetic coupling of phosphoramidites prepared from (L)-DPSE or (L)-PSM gives rise to phosphorothioate diester linkages of Sp chirality and phosphoramidate diester linkages of Rp chirality, respectively, and those prepared from (D)-DPSE or (D)-PSM gives rise to phosphorothioate diester linkages of Rp chirality and phosphoramidate diester linkages of Sp chirality.
  • Consistent use of stereodefined phosphoramidites for each coupling reaction allows for control of stereochemical identity of each phosphorothioate linkage. Stereochemical identity can be confirmed using various technologies in accordance with the present disclosure.
  • stereochemical identity can be confirmed by measurement using several different techniques, which in combination, and by comparison with appropriate standards, provides accurate information about, and confirmation of, this key attribute.
  • Useful analytical techniques include NMR ( 1 H, 19 F, 31 P, multidimensional, etc.) and enzymatic digestion. In some instances, NMR are performed in phosphate buffer (e.g., pH 7.0). Results including 1 H, 19 F and 31 P NMR and enzymatic digestion of various preparations are consistent with product structures. In some embodiments, NMR is referenced to water based on DSS standard. Observed data from certain experiments are described below.
  • WVE-003 drug substance was prepared at a concentration of 1 mM in 600 ⁇ L of 100 atom% D 2 O solution containing 100 mM NaCl, 0.05 mM EDTA and 10 mM phosphate buffer (pH 7.0).
  • spectra were recorded at 334 K.
  • sodium trimethylsilylpropanesulfonate (DSS) in phosphate buffer was used as an external reference standard.
  • 1 H NMR spectra were calibrated indirectly based on DSS peak at 0 ppm. The 1 H NMR spectrum contains signals consistent with the WVE-003 structure and the chemical shifts of the individual regions of signals are consistent with the proposed structure.
  • 31 P NMR spectra were calibrated indirectly using the united scale based on 1 H NMR spectra of external standard where DSS peak was set as 0 ppm.
  • a sharp signal around 2 ppm is 91 of 265 12842751v1 Attorney Docket No.: 2010581-1510 coming from the phosphate buffer used.
  • the total of 19 PS/PN/PO peaks are consistent with the stereodefined mixed PO/PS/PN backbone of WVE- 003 drug substance.
  • stereoc em ca dent ty o WVE-003 was con rmed by enzymat c djust assay.
  • stereochemical purity is presented as the percentage of correct diastereomer associated with the assigned stereochemical identity to the total diastereomeric mixture. This is inclusive of small quantities of other diastereomers that may be present.
  • each (L)- or (D)-DPSE phosphoramidite to its stereodefined phosphorothioate or phosphoramidate linkage in WVE-003 is very high and the overall stereochemical purity of the oligonucleotide is a product of the combination of the diastereoselectivities of these 13 phosphorothioate and 4 phosphoramidate linkages.
  • diastereoselectivities of chiral linkages are assessed through preparation of corresponding dimers. The synthesis conditions used to produce each sequence dimer are identical to those applied to the whole molecule.
  • WVE-003 sequence dimers and their respective references were analyzed by Ultra Performance Liquid Chromatography (UPLC) for purity and/or by Ultra Performance Liquid Chromatography – Mass Spectrometry (UPLC-MS) for mass confirmation of Sp and Rp diastereomers.
  • UPLC Ultra Performance Liquid Chromatography
  • UPLC-MS Ultra Performance Liquid Chromatography – Mass Spectrometry
  • UPLC analysis is utilized in dimer modeling. As demonstrated herein, all 17 linkages are ⁇ 97% stereopure, 9 linkages are ⁇ 97% stereopure, and 7 linkages are ⁇ 99% stereopure. In some embodiments, as demonstrated herein, an average stereochemical purity of all linkages is 98.9%.
  • a reference standard e.g., one characterized by NMR, enzymatic digestion, etc. is used to determine stereochemical identity by UPLC as part of batch release. In some embodiments, the provided technology provides reference standards.
  • a reference standards has purity (e.g., as assessed by Protocol A) and/or stereopurity (e.g., as assessed by Protocol B and/or dimer modeling as described herein).
  • FTIR spectrum of WVE-003 was obtained with an attenuated total reflectance (ATR) sampling accessory, with major absorbance bands at 1636 cm -1 and 1600 cm -1 , absorption peak at 2938 cm -1 , and broad peaks at 3199 cm -1 and 3339 cm -1 . The FTIR results is consistent with the structure of WVE-003.
  • Counter ions can be analyzed in accordance with the present disclosure. In some embodiments, sodium content is assessed by ICP-OES.
  • a sodium content value of 4.5% has been determined by ICP-OES for a WVE-003 drug substance, which is in agreement with the theoretical sodium content value of 4.5% (w/w).
  • WVE-003 drug substance is a white to off-white powder.
  • the pH of WVE-003 drug substance in purified water was found to be 6.0-8.0. In some embodiments, it is about 6.5-7.5. In some embodiments, it is about 6.4. In some embodiments, it is about 6.5. In some embodiments, it is about 6.6. In some embodiments, it is about 6.7. In some embodiments, it is about 6.8. In some embodiments, it is about 6.9. In some embodiments, it is about 7.0.
  • impurities are controlled at low levels as described herein. For example, in some embodiments, impurity level is lower than about 30%, about 25%, or about 20% as described herein.
  • impurities include various oligonucleotide impurities.
  • Various technologies may be utilized to identify, characterize and/or assess impurities, e.g., mass spectrometry, LC, UV, etc.
  • WVE-003 drug substance was assessed in GLP in vitro genotoxicity studies and in an in vivo micronucleus study. No toxicity was observed.
  • Release specifications of WVE-003 drug substance and/or drug product may include one or more specifications described herein, e.g., appearance (e.g., visual, white to off white powder), sequence identity (e.g., by MS/MS), molecular weight, stereochemical identity (e.g., IP-RP-UPLC), purity (e.g., area % by IP- RP-UPLC (e.g., Protocol A)), impurities (e.g., area % by IP-RP-UPLC (e.g., Protocol A)), sodium content (e.g., by ICP-OES, etc.), water content (% w/w; e.g., USP ⁇ 921> and/or Ph.
  • appearance e.g., visual, white to off white powder
  • sequence identity e.g., by MS/MS
  • molecular weight stereochemical identity
  • stereochemical identity e.g., IP-RP-UPLC
  • purity e.g., area % by IP-
  • assay e.g., free acid, anhydrous, by UV
  • pH e.g., of solution in purified water; e.g., USP ⁇ 791> and/or Ph. Eur.2.2.3, etc.
  • residual solvents e.g., by gas chromatography
  • elemental impurities e.g., by ICP-MS
  • bacterial endotoxins e.g., by USP ⁇ 85> and/or Ph. Eur 2.6.14
  • bioburden total microbial aerobic count, total yeast and bolds count, etc. by USP ⁇ 61>
  • Ph. Eur 2.6.12 etc.
  • the identity of WVE-003, e.g., a drug substance is determined by liquid chromatography mass spectrometry (LC-MS).
  • LC-MS liquid chromatography mass spectrometry
  • Samples and analytical reference material are prepared in water and injected on a Waters Acquity BEH C18 column. Analysis involves a gradient of mobile phase A (hexafluoroisopropanol [HFIP] and triethylamine [TEA] in water) and mobile phase B (acetonitrile).
  • the sodium content of WVE-003 preparation e.g., drug substance
  • Sample material in solution is introduced by pneumatic nebulization into radio frequency plasma where energy transfer processes cause desolvation, atomization, and ionization.
  • a sodium content (anhydrous basis) is about 3.9-5.2% (w/w). In some embodiments, it is about 4-5%. In some embodiments, it is about 4.3%- 4.7%.
  • the present disclosure provides technologies for assessing purity and/or impurities of a WVE-003 preparation or composition.
  • purity and impurities of WVE- 003 drug substance are determined by ion-pair reversed-phase UPLC (IP-RP-UPLC) using a Waters BEH C18 Column. A useful procedure is described below as example (Protocol A).
  • system suitability is established by the absence of interfering peaks in the blank as well as acceptance criteria for %RSD for retention time, peak area% and peak area for the initial injections and all injections of WVE-003 analytical reference material (system suitability standard).
  • all individual impurities ⁇ 0.10 area%, as a function of relative retention time to the main peak, as well as total of all impurities ⁇ 0.10 area% are reported.
  • WVE-003 identity is confirmed by comparing relative retention time with system suitability standard.
  • the method has been determined to be stability indicating in method development studies.
  • Parameter Value 12842751v1 Attorney Docket No.: 2010581-1510 30 94 6 1 etc. is about 84% or more (e.g., assessed by Protocol A (% area)). In some embodiments, it is about 85% or more. In some embodiments, it is about 86% or more. In some embodiments, it is about 87% or more. In some embodiments, it is about 88% or more. In some embodiments, it is about 80%-90%. In some embodiments, it is about 84%-90%. In some embodiments, it is about 84%-88%.
  • total impurities are about or no more than about 16% (e.g., assessed by Protocol A (% area)). In some embodiments, total impurities are about or no more than about 15%. In some embodiments, total impurities are about or no more than about 14%. In some embodiments, total impurities are about or no more than about 13%. In some embodiments, total impurities are about or no more than about 12%. In some embodiments, sum of WVE-003 and total impurities is about 99%-101%. As described herein, in various embodiments, amount of WVE-003 in a composition, preparation, dose, drug product, etc.
  • assay of a WVE-003 preparation e.g., a drug substance, a drug product, etc.
  • assay of a WVE-003 preparation is determined by UV spectrophotometry.
  • a useful procedure is described herein as an example.
  • a quantity of WVE-003 drug substance is accurately weighed and dissolved in water in volumetric glassware.
  • the solution absorbance is determined at 260 nm, and this value is converted to a concentration of WVE-003 drug substance using the molar extinction coefficient (MEC; 181,181 M -1 cm -1 and 25.0 OD/mg).
  • the quantity of the weighed material is corrected by subtraction of the water content of the sample (e.g., by Karl Fischer titration USP ⁇ 921> Method 1c) and subtraction of the sodium content.
  • the Assay (%) is then determined as a ratio of the WVE- 003 quantity measured by absorbance to the theoretical prepared quantity based on the accurate weight of the sample corrected for water and sodium content.
  • assay of a WVE-003 preparation e.g., a drug substance, a drug product, etc., is about 100% ⁇ 10%. In some embodiments, it is about 95%-105%. In some embodiments, it is about 95%. In some embodiments, it is about 96%. In some embodiments, it is about 97%.
  • water content of a WVE-003 preparation e.g., a drug substance, a drug product, etc.
  • water content of a WVE-003 preparation is determined by coulometric titration (Karl Fischer). In some embodiments, system suitability is established by required adequate recovery from a sodium tartrate monohydrate certified control standard of known water content.
  • water content of a WVE-003 preparation e.g., a drug substance, a drug product, etc., is no more than about 15%, 10%, 5% or 1% (w/w). In some embodiments, it is no more than about 15%. In some embodiments, it is no more than about 10%.
  • residual solvents within a WVE-003 preparation e.g., a drug substance, a 98 of 265 12842751v1 Attorney Docket No.: 2010581-1510 drug product, etc. are quantified using gas chromatography with flame ionization detection (GC-FID).
  • GC-FID gas chromatography with flame ionization detection
  • samples are prepared by being mixed well, weighed into crimped vials and dissolved in solvent. Sample is then introduced via direct injection and quantitation is performed as a limit test by comparison to an external standard. Blanks and calibration verifications are analyzed at appropriate intervals.
  • the present disclosure provides technologies for confirming stereochemical identity of WVE-003 or a diastereomer thereof (e.g., with respect to one or more chiral linkage phosphorus centers).
  • stereochemical identity of WVE-003, e.g., in a WVE-003 preparation, a drug substance, a drug product, etc. is determined by IP-RP-UPLC using a Waters BEH C18 Column.
  • Method B A useful procedure is described below as an example (Protocol B).
  • the separation of WVE-003 from closely related diastereomeric impurities is provided using a gradient of mobile phase A (triethylamine acetate [TEAA] in water) and mobile phase B (50% acetonitrile in water).
  • TEAA triethylamine acetate
  • Set B parameters A summary of method parameters is provided below (Set B parameters).
  • system suitability is established by the absence of interfering peaks in the blank as well as acceptance criteria for %RSD for retention time and peak area for the initial injections of WVE-003 analytical reference material, for % difference between the trailing standard peak area and the average of the initial injections of standard, and %RSD for retention time for all standard injections.
  • a WVE-003 preparation, composition, dose, drug substance, drug product, etc. may comprise one or more linkage phosphorus diastereomers (e.g., if after purification, to the extent that the purification cannot remove one or more diastereomers).
  • Parameter Value 12842751v1 Attorney Docket No.: 2010581-1510 51 40 60 6 52 68 32 1 ur. 2.6.14.
  • bioburden e.g., both total aerobic microbial count (TAMC) and total yeast and mold counts (TYMC)
  • TAMC total aerobic microbial count
  • TYMC total yeast and mold counts
  • WVE-003 drug substance is packaged in a suitable container, e.g., sterile high-density polyethylene (HDPE) bottles with polypropylene screw closures, labeled and sealed in a protector, e.g., Mylar foil pouches which can provide a gas/moisture barrier with high levels of abrasion and puncture resistance.
  • a suitable container e.g., sterile high-density polyethylene (HDPE) bottles with polypropylene screw closures, labeled and sealed in a protector, e.g., Mylar foil pouches which can provide a gas/moisture barrier with high levels of abrasion and puncture resistance.
  • a protector e.g., Mylar foil pouches which can provide a gas/moi
  • WVE-003 or a composition thereof is stored at about -20 oC.
  • a long-term storage condition is at about -20oC, e.g. ⁇ 5oC.
  • a storage is at about 5oC, e.g., ⁇ 3oC.
  • Drug Product [0440]
  • a WVE-003 drug product comprises a WVE-003 drug substance, e.g., WVE-003 pentadecasodium salt manufactured using a process described above.
  • a WVE-003 drug product consists of WVE-003 drug substance, e.g., WVE-003 pentadecasodium salt, as a lyophilized solid in a vial.
  • a vial is a 10 mL vial.
  • a vial is a 10 mL USP/Ph. Eur. Type 1 clear glass vial sealed with a FluroTec ® coated elastomeric rubber stopper and an aluminum overseal with a blue matte flip-off button.
  • a vial contains WVE-003 for a single dose as described herein.
  • a vial contains WVE-003 equivalent to about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg WVE-003 free acid form.
  • a vial contains about 20 mg WVE-003 (unless specified otherwise, based on free acid form).
  • a vial contains about 30 mg WVE-003.
  • a vial contains about 60 mg WVE-003.
  • a vial contains about 90 mg WVE-003.
  • vials filled with 2.53 mL of WVE-003 drug substance at 8 mg/mL concentration in water for injection are lyophilized and backfilled with nitrogen gas, NF upon completion of the lyophilization cycle.
  • a WVE-003 drug product vial contains about 20 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 30 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 40 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 50 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 60 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 70 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 80 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 90 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 100 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 110 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 120 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 130 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 140 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 150 mg of WVE-003 drug substance. In some embodiments, a WVE-003 drug product vial contains about 160 mg of WVE-003 drug substance.
  • a WVE-003 drug product vial contains about 170 mg of WVE-003 drug substance.
  • a drug substance is WVE-003 pentadecasodium salt.
  • a vial contains about 31 mg WVE-003 pentadecasodium salt; in some embodiments, a vial contains about 62 mg WVE-003 pentadecasodium salt; in some embodiments, a vial contains about 94 mg WVE-003 pentadecasodium salt. In some embodiments, a vial contains 31.4 mg WVE-003 pentadecasodium salt.
  • a vial contains 62.7 mg WVE-003 pentadecasodium salt. In some embodiments, a vial contains 94.1 mg WVE-003 pentadecasodium salt. In some embodiments, the present disclosure provides a pharmaceutical composition comprising or delivering WVE-003 or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition consists of a WVE-003 drug substance and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier is aCSF.
  • each WVE-003 drug product vial contains WVE-003 drug substance for a single dose.
  • WVE-003 drug substance is reconstituted and diluted in artificial cerebral spinal fluid (aCSF) as a sterile, preservative-free solution at the clinical site prior to intrathecal administration.
  • a pharmaceutical composition is WVE-003 dissolved in aCSF.
  • a pharmaceutical composition is WVE-003 pentadecasodium salt dissolved in aCSF.
  • the amount of WVE-003 in or delivered by a composition is equivalent to about 30 mg WVE-003 acid form.
  • the amount of WVE-003 in or delivered by a composition is equivalent to about 60 mg WVE-003 acid form. In some embodiments, the amount of WVE-003 in or delivered a composition is equivalent to about 90 mg WVE-003 acid form. In some embodiments, the amount of aCSF in a composition is about 20 mL. In some embodiments, the present disclosure provides a device, e.g., a container, a syringe (e.g., a 20-mL polypropylene syringe), etc., containing a pharmaceutical composition as described herein.
  • a device e.g., a container, a syringe (e.g., a 20-mL polypropylene syringe), etc., containing a pharmaceutical composition as described herein.
  • the present disclosure provides a device, e.g., a container, a syringe (e.g., a 20-mL polypropylene syringe), etc., for delivering WVE-003, a composition, e.g., a pharmaceutical composition, or a 101 of 265 12842751v1 Attorney Docket No.: 2010581-1510 dose, as described herein.
  • a device is for intrathecal administration.
  • a device contains a dose of WVE-003, e.g., about 30 mg, 60 mg or 90 mg, as described herein.
  • a device is for administration or delivery of a dose of WVE-003, e.g., about 30 mg, 60 mg or 90 mg, as described herein. In some embodiments, a device is for intrathecal administration or delivery of a dose of WVE-003, e.g., about 30 mg, 60 mg or 90 mg, as described herein.
  • a WVE- 003 composition e.g., a drug product, contains no preservatives, inactive ingredients, or excipients. [0441]
  • WVE-003 drug product is a white to off-white solid with no visible material and essentially free of particulates upon reconstitution.
  • pH of a 20 mg WVE-003 in 2 mL artificial cerebrospinal fluid (aCSF) solution is about 6.0 – 8.0. In some embodiments, pH of a 20 mg WVE-003 in 2 mL aCSF solution is about 6.4 – 7.2.
  • a freezing temperature at about -45 °C, primary and secondary drying temperatures at about -14 °C and 25 °C, and 100 mTorr pressure are utilized. Other skilled in the art appreciate that other temperatures and/or pressure may also be utilized.
  • approximately 75 grams of WVE-003 drug substance is formulated with water for injection, Ph. Eur.
  • a drug product lot may be made by pooling multiple drug substance lots.
  • the total number of vials calculated from the amount of drug substance is as follows: The purity, sodium content, and water content of drug substance was 86%, 4.3%, and 8%, respectively.
  • the drug substance (DS) amount used for manufacturing drug product (DP) batch is 75.04 g.
  • the total number of vials and batch volume calculated from the amount of drug substance is as follows: The purity, sodium content, and water content of drug substance was 86%, 4.3%, and 8%, respectively.
  • the drug substance (DS) amount used for manufacturing drug product (DP) batch is 75.04 g.
  • Theoretical Batch Volume (mL) Theoretical total DS in mg x (Purity by UPLC (%))/100%) x [(100% - Sodium Content (%) – Water Content (%))/100%] ⁇ Concentration 102 of 265 12842751v1 Attorney Docket No.: 2010581-1510
  • WVE-003 drug substance (DS) containers are thawed at 2-8°C followed by equilibrating at room temperature (RT).
  • pure full-length product is calculated as: purity 100% sodium content% 100% moisture% Pure FLP DS g x % x x 100 100% 100%
  • a pure full-length product is calculated as: purity 100% sodium content% moisture% Pure FLP DS g x % x 100 100%
  • UPLC as described herein
  • sodium content % e.g., ICP-OES as described herein
  • moisture % e.g., Karl Fischer (e.g., USP ⁇ 921>) as described herein), etc.
  • Karl Fischer e.g., USP ⁇ 921>
  • a purity correction factor that is based on the quantity of DS from each lot is determined.
  • the batch volume to manufacture 8 mg/mL solution is calculated.
  • WFI in the amount of ⁇ 50% of the calculated batch volume is added to the formulation vessel by weight.
  • the DS containers are weighed and DS from each container is transferred into the formulation vessel. Appropriate WFI rinses are used to ensure complete removal of DS from containers.
  • the empty DS containers are dried and weighed to calculate total DS added to the formulation vessel.
  • the DS is mixed adequately and an in-process sample to measure concentration by ultraviolet (UV) assay is taken. The remaining solution mass in the formulation is weighed.
  • UV ultraviolet
  • the required amount of WFI to accomplish WVE-003 drug substance final concentration of 8.0 mg/mL is calculated as follows: mg Solution mass g conc. Solution mass g [0447] Required of WFI is then slowly added directly to the formulation vessel and mixed to ensure homogenous solution is formed. In-process samples are collected for appearance, concentration by UV spectrophotometry, and density, which should meet various specifications.
  • This final compounded formulation 103 of 265 12842751v1 Attorney Docket No.: 2010581-1510 undergoes bioburden reduction filtration following which it can be stored overnight at 2-8°C, if required.
  • a pre-filtration bioburden sample is taken prior to sterile filtration of the compounded bulk solution.
  • the final compounded formulation is sterile filtered through two 0.2 ⁇ m filters in series prior to filling. Sterile filter units are checked for filter integrity by bubble point method prior to and post filtration.
  • the target fill weight is determined based on target fill volume of 2.53 mL and measured density. Filling occurs with periodic fill checks and filled vials with stoppers in lyo-position are placed on lyophilization- trays. HEPA carts are used for aseptic transfer of lyophilization-trays into the sterilized lyophilizer.
  • lyophilization cycle parameters are those provided below.
  • a primary control of critical steps during the manufacture of WVE- 003 drug product is exerted via in-process concentration measurements via ultraviolet (UV) spectrophotometry.
  • the in-process concentration measurement is used to calculate the amount of WFI required to dilute compounding solution to a final concentration of 8 mg/mL WVE-003 drug substance. Appropriate dilution is confirmed by measuring the concentration of final bulk drug solution.
  • Microbial control is exerted by measuring pre-filtration bioburden and analyzing pre- and post-filtration integrity of the sterilizing filters.
  • Drug product filled vials are subjected to periodic weight checks during the filling process and 100% visual inspection prior to sampling for release, bulk packaging, and/or stability.
  • Release specifications of WVE-003 drug product may include one or more specifications described herein, e.g., appearance (e.g., visual; white to off white solid), appearance after reconstitution (e.g., visual), identity (e.g., by LC-MS, retention time of IP-RP-UPLC, mass, etc.), purity (e.g., area % by IP-RP-UPLC (e.g., Protocol A)), impurities (e.g., area % by IP-RP-UPLC (e.g., Protocol A)), assay (e.g., % label claim; e.g., free acid, anhydrous, by UV), pH (e.g., after reconstitution: reconstitute 20 mg vial with 2 mL of aCSF diluent; e.g., 104 of 265 12842751v1 Attorney Docket No.: 2010581-1510 USP ⁇ 791> and/or Ph.
  • appearance e.g., visual; white
  • osmolality e.g., after reconstitution: reconstitute 20 mg vial with 2 mL of aCSF diluent; e.g., USP ⁇ 791> and/or Ph. Eur. 2.2.3
  • bacterial endotoxin e.g., USP ⁇ 85> and/or Ph. Eur. 2.6.14
  • sterility e.g., USP ⁇ 71> and/or Ph. Eur. 2.6.1
  • uniformity of dose e.g., USP ⁇ 905> and/or Ph. Eur. 2.9.40
  • particulate matter e.g., USP ⁇ 788> and/or Ph. Eur.
  • a WVE-003 drug product demonstrates about the same or similar specification, e.g., purity, impurities, pH, water content, etc. as a WVE-003 drug substance as described herein.
  • purity of a WVE-003 drug product is about 84% or more (e.g., assessed by Protocol A (% area)).
  • total impurities are about or no more than about 16% (e.g., assessed by Protocol A (% area)). In some embodiments, total impurities are about or no more than about 15%. In some embodiments, total impurities are about or no more than about 14%. In some embodiments, total impurities are about or no more than about 13%.
  • total impurities are about or no more than about 12%. In some embodiments, total impurities are about or no more than about 11%. In some embodiments, sum of WVE-003 and total impurities is about 99%-101%.
  • the assay (% label claim) of the WVE-003 drug product is determined by ultraviolet (UV) spectrophotometry. Test samples are reconstituted with water, then quantitatively transferred to a volumetric flask and diluted to volume with water.
  • the absorbance of the solution at 260 nm is measured and used, along with molar extinction coefficient (MEC), and the experimentally measured WVE-003 purity, to determine the amount of purity corrected WVE-003 drug substance per vial (mg/vial), which is then compared to the expected amount in vial, e.g., 20 mg, to obtain % label claim.
  • assay sample preparation and calculations are performed as described below: Finished product vial is reconstituted with 2.5 mL of water to obtain a solution of 8 mg/mL.
  • Stock Sample (0.1 mg/mL): Pipette (in duplicate) 0.32 mL of 8 mg/mL drug product into a 25 mL volumetric flask, QS with water and mix well.
  • Working Sample (0.02 mg/mL): From each 0.1 mg/mL stock sample solution pipette 2.0 mL into a 10 mL volumetric flask. Dilute to volume with water and mix well. Each working sample is analyzed at 260 nm (A260) with 1 reading (1 cm cuvette).
  • % label claim is about 100% ⁇ 10%. In some embodiments, it is about 95%-105%. In some embodiments, it is about 95%. In some embodiments, it is about 96%. In some embodiments, it is about 97%.
  • it is about 98%. In some embodiments, it is about 99%. In some embodiments, it is about 100%. In some embodiments, it is about 101%. In some embodiments, it is about 102%. In some embodiments, it is about 103%. In some embodiments, it is about 104%. In some embodiments, it is about 105%. In some embodiments, it is about 106%. In some embodiments, it is about 107%. In some embodiments, it is about 108%. In some embodiments, it is about 109%. In some embodiments, it is about 110%.
  • reconstitution time of WVE-003 drug product is determined visually upon reconstitution with 2 mL sterile, preservative-free aCSF and gentle inversion until the cake is completely dissolved. The time it takes to completely reconstitute the cake is determined using a calibrated timer.
  • the uniformity of WVE-003 drug product dosage units is determined by UV content uniformity method. The uniformity of WVE-003 drug product dosage units is determined by reconstitution of ten vials, and if necessary, an additional twenty vials are tested. The assay (% label claim) is determined by UV spectrophotometry, as described above, for each vial.
  • particulate matter in WVE-003 drug product is determined by reconstitution of 10 vials with 10 mL purified water, then pooling of the resulting solutions for analysis The pooled solution is then analyzed using a particle counter per the Test 1.B light obscuration test to determine the number of particles 10 ⁇ m or greater and 25 ⁇ m or greater in this solution. Calibration verification is performed prior to test sample analysis.
  • a WVE-003 drug product diluted in aCSF
  • a reconstitution medium e.g., aCSF
  • a WVE-003 drug product is stored at about 5°C, e.g., ⁇ 3°C. In some embodiments, it is stored at about 25°C, e.g., ⁇ 2°C. In some embodiments, it can be stored at about 40°C, e.g., ⁇ 2°C.
  • a WVE-003 drug product is stable for about 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, or more months. In some embodiments, a WVE-003 drug product is stable for about 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 or more months at about 5°C, e.g., ⁇ 3°C. In some embodiments, a WVE-003 drug product is stable for about 6, 9, 12, 15, 18, 21, 24 or more months at about 25°C, e.g., ⁇ 2°C (e.g., 60% RH ⁇ 5%).
  • a WVE-003 drug product is stable for about 1, 2, 3, 4, 5, 6 or more months at about 40°C, e.g., 106 of 265 12842751v1 Attorney Docket No.: 2010581-1510 ⁇ 2°C (e.g., 75% RH ⁇ 5%).
  • WVE-003 is provided in a solution composition, e.g., dissolved in aCSF.
  • diluent to be used as placebo and diluent for the reconstitution of WVE-003 (drug product vials) is an artificial cerebrospinal fluid (aCSF) solution. In some embodiments, it is in a 20 mL USP/ Ph.
  • a vial contains 20.8 mL of aCSF (which includes 0.8 mL overfill above the nominal fill volume of 20 mL).
  • pH of a diluent e.g., aCSF
  • composition of diluent is as presented below: Component Quality Standard Possible Amount per vial Concentration Function mg/mL 107 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Water for Injection Ph.
  • the present disclosure provides a formulation of a HTT oligonucleotide, e.g., WVE-003.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is or is of WVE-003.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • the present disclosure provides a chirally controlled HTT oligonucleotide composition is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is provided as a lyophilized powder for reconstitution and dilution for administration.
  • WVE-003 preparations or formulations are in the form of a white to off-white lyophilized solid.
  • solubility of WVE-003 drug substance in water determined to be at least 79.20 mg/ mL as determined by UV spectrophotometry.
  • the pH of WVE-003 drug substance in purified water ranges from 6.0-8.0.
  • a HTT oligonucleotide, or a salt form thereof, or a HTT oligonucleotide composition is provided as a liquid formulation.
  • WVE-003 has been formulated as a lyophilized powder for reconstitution and dilution for administration. In some embodiments, WVE-003 has been formulated as a as a liquid formulation.
  • the present disclosure provides a particular formulation of WVE-003. In some embodiments, the present disclosure provides a method of use of a particular formulation of WVE-003 at a dosage of about 30, about 60, about 90, about 120, about 150 or about 168 mg in treatment of Huntington’s disease.
  • a HTT oligonucleotide is WVE-003.
  • the present disclosure pertains to: A method of treatment of Huntington’s disease in a subject in need thereof, wherein the subject is administered a HTT oligonucleotide which is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation with a solution of sodium chloride. 108 of 265 12842751v1 Attorney Docket No.: 2010581-1510 [0468]
  • a lyophilized preparation of WVE-003 is a dry powder.
  • a lyophilized preparation of WVE-003 is a dry powder prepared by lyophilization of a liquid formulation of WVE-003 in water.
  • a lyophilized preparation of WVE-003 is a dry powder in a vial.
  • a lyophilized preparation of WVE-003 is about 20 mg of a dry powder in a vial.
  • a lyophilized preparation of WVE-003 is a dry powder in a 10 ml vial.
  • a lyophilized preparation of WVE-003 is about 20 mg of a dry powder in a 10 ml vial.
  • the reconstituted solution does not contain any preservatives; therefore, it should be administered without delay. If this is not possible, the solution should be stored at room temperature and administered within 4 hours.
  • Partially used, unused, or damaged vials should be disposed of.
  • HTT oligonucleotides WVE-003 were analyzed in nonclinical and clinical studies.
  • WVE-003 is provided in a solution. In some embodiments, WVE-003 is administered in a solution.
  • WVE-003 is dissolved in a suitable diluent.
  • a diluent is aCSF.
  • a WVE-003 composition is a WVE-003 preparation (e.g., drug substance, drug product, etc.) dissolved in aCSF.
  • Dosing Regimen of a HTT Oligonucleotide [0478]
  • a dosing regimen of an oligonucleotide, an oligonucleotide composition, a chirally controlled oligonucleotide composition, or a therapeutically effective amount of any thereof is any dosing regimen described herein.
  • a dosing regimen pertains to: the amount of an individual dose of an oligonucleotide, an oligonucleotide composition, a chirally controlled oligonucleotide composition, or a therapeutically effective amount of an oligonucleotide, an oligonucleotide composition, a chirally controlled oligonucleotide composition; and/or the interval between multiple or successive doses thereof; and/or the total length or duration of time during which a subject receives one or more doses thereof; and/or a particular formulation thereof.
  • a dosing regimen of WVE-003, an oligonucleotide composition of WVE- 003, a chirally controlled oligonucleotide composition of WVE-003, or a therapeutically effective amount of WVE-003, an oligonucleotide composition of WVE-003, a chirally controlled oligonucleotide composition of WVE-003, or a therapeutically effective amount of an oligonucleotide composition of WVE-003, a chirally controlled oligonucleotide composition of WVE-003, or a therapeutically effective amount of WVE-003, an oligonucleotide composition of WVE-003, a chirally controlled oligonucleotide composition of WVE-003 is 109 of 265 12842751v1 Attorney Docket No.: 2010581-1510 any dosing regimen described herein.
  • a dosing regimen includes but is not limited to a specific amount (e.g., about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, and/or about 168 mg per dose, per dosage, and/or per administration) and/or particular dosing intervals (e.g., once about every 4 weeks, once about every 8 weeks, once about every 12 weeks, once about every month, once about every 2 months, etc.), and/or particular lengths or durations of dosing (e.g., dosing occurs over a span of time of at least: about 1 month, about 2 month, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 36 months, about 48 months, and/or at least: about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks
  • a dosing regimen is any dosing regimen described herein. In some embodiments, a dosing regimen is or comprises a dosing regimen described in the Examples.
  • a dose of WVE-003 e.g., about 30, about 60, about 90, about 120, about 150 or about 168 mg
  • a dose of WVE-003 is administered approximately monthly. In some embodiments, a dose of WVE-003 is administered approximately once every 2 months. In some embodiments, a dose of WVE-003 is administered approximately once every 8 weeks.
  • a dose of WVE- 003 is administered approximately once every 12 weeks. [0483] In some embodiments, a dose of WVE-003 is administered approximately monthly for at least about three months. In some embodiments, a dose of WVE-003 is administered approximately once every 2 months for at least about four months. In some embodiments, a dose of WVE-003 is administered approximately once every 8 weeks for at least about 16 weeks. In some embodiments, a dose of WVE-003 is administered approximately once every 12 weeks for at least about 12 weeks.
  • a dose of WVE-003 is administered approximately monthly, and preceding the first monthly dose, WVE-003 is administered, followed by an approximately 8-week (approximately 2- month) washout period.
  • a dose of WVE-003 is administered approximately once every 2 months, and preceding the first once every 2 months dose, WVE-003 is administered, followed by an approximately 12-week (approximately 3-month) washout period.
  • a dose of WVE-003 is administered approximately once every 8 weeks, and preceding the first once every 8 weeks dose, WVE-003 is administered, followed by an approximately 12-week (approximately 3-month) washout period.
  • a dose of WVE-003 is administered, followed by an approximately 8-week (approximately 2-month) washout period, followed by approximately monthly doses of WVE-003.
  • a dose of WVE-003 is administered, followed by an approximately 12-week (approximately 3- month) washout period, followed by approximately once every 2 months doses of WVE-003.
  • a dose of WVE-003 is administered, followed by an approximately 12-week (approximately 3- month) washout period, followed by approximately once every 8 weeks doses of WVE-003.
  • a lumbar puncture (spinal tap) procedure is performed to obtain CSF for analysis after one or more doses of the oligonucleotide.
  • a lumbar puncture (spinal tap) procedure is performed to obtain CSF for analysis after approximately 1 month (approximately 4 weeks) after the third monthly dose.
  • the present disclosure provides a method for selectively reducing level of mHTT protein over wtHTT protein in a subject, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • the present disclosure provides a method for selectively reducing level of mHTT protein over wtHTT protein in CSF in a subject, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein. In some embodiments, the present disclosure provides a method for slowing caudate atrophy in a subject, wherein the method comprises administering or delivering to the subject WVE- 003 according to a dosing regimen provided herein. In some embodiments, the present disclosure provides a method for reducing TMS of a subject, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a subject, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • the present disclosure provides a method for selectively reducing level of mHTT protein over wtHTT protein in a population of subjects, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • the present disclosure provides a method for selectively reducing level of mHTT protein over wtHTT protein in CSF in a population of subjects, wherein the method comprises administering or delivering to the subject WVE- 003 according to a dosing regimen provided herein. In some embodiments, the present disclosure provides a method for slowing caudate atrophy in a population of subjects, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein. In some embodiments, the present disclosure provides a method for reducing TMS in a population of subjects, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • the present disclosure provides a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects, wherein the method comprises administering or delivering to the subject WVE-003 according to a dosing regimen provided herein.
  • a dose of WVE-003 is administered approximately once about every 8 weeks or less frequently.
  • a dose of WVE-003 is administered approximately once about every 8 weeks.
  • a dose of WVE-003 is administered approximately once about every 12 weeks or less frequently.
  • a dose of WVE-003 is administered approximately once about every 12 weeks.
  • a dose of WVE-003 is administered approximately once about every quarter or less frequently.
  • a dose of WVE-003 is administered approximately once 111 of 265 12842751v1 Attorney Docket No.: 2010581-1510 about every quarter.
  • one or more doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of WVE-003 are administered about every 8 weeks or less frequently.
  • two or more doses of WVE- 003 are administered about every 8 weeks or less frequently.
  • three or more doses of WVE-003 are administered about every 8 weeks or less frequently.
  • one or more doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of WVE-003 are administered about every 12 weeks or less frequently.
  • two or more doses of WVE-003 are administered about every 12 weeks or less frequently. In some embodiments, three or more doses of WVE-003 are administered about every 12 weeks or less frequently. In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE- 003 are administered about quarterly or less frequently. In some embodiments, two or more doses of WVE- 003 are administered about quarterly or less frequently. In some embodiments, three or more doses of WVE- 003 are administered about quarterly or less frequently. In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE-003 are administered about quarterly.
  • two or more doses of WVE-003 are administered about quarterly. In some embodiments, three or more doses of WVE-003 are administered about quarterly. [0492] In some embodiments, a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE- 003 are administered or delivered about every 8 weeks or less frequently. In some embodiments, a set of three or more doses of WVE-003 are administered or delivered about every 8 weeks or less frequently. In some embodiments, a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE-003 are administered or delivered about every 12 weeks or less frequently.
  • a set of three or more doses of WVE-003 are administered or delivered about every 12 weeks or less frequently. In some embodiments, a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE-003 are administered or delivered about quarterly or less frequently. In some embodiments, a set of three or more doses of WVE-003 are administered or delivered about quarterly or less frequently. In some embodiments, a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses are administered or delivered about quarterly. In some embodiments, a set of three or more doses are administered or delivered about quarterly.
  • one or more doses of WVE-003 are administered or delivered to a subject before a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE-003. In some embodiments, one or more doses of WVE-003 are administered or delivered to a subject before a set of three or more doses of WVE-003. [0493] In some embodiments, level of mHTT protein in CSF of a subject is reduced by 30% or more compare to a reference level of mHTT protein in CSF.
  • level of mHTT protein is assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses. In some embodiments, level of mHTT protein is assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, level of mHTT protein is assessed about 28 days after a last dose of a set of doses. In some embodiments, level of mHTT protein is assessed about 56 days after a last dose of a set of doses.
  • level of mHTT protein is assessed about 84 days after a 112 of 265 12842751v1 Attorney Docket No.: 2010581-1510 last dose of a set of doses.
  • a reference level of mHTT protein is or comprises a baseline level.
  • level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF.
  • level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 28, 56, or 84 days after a last dose of a set of doses.
  • level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 28 days after a last dose of a set of doses. In some embodiments, level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 56 days after a last dose of a set of doses. In some embodiments, level of mHTT protein in CSF of a subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 84 days after a last dose of a set of doses.
  • level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF.
  • level of wtHTT protein is assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • level of wtHTT protein is assessed about 28 days after a last dose of a set of doses.
  • level of wtHTT protein is assessed about 56 days after a last dose of a set of doses.
  • level of wtHTT protein is assessed about 84 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF if assessed about 28, 56, or 84 days after a last dose of a set of doses.
  • level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF if assessed about 28 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF if assessed about 56 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is not reduced compared to a reference level of wtHTT protein in CSF if assessed about 84 days after a last dose of a set of doses.
  • a reference wtHTT protein level is or comprises a baseline level.
  • level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF.
  • level of wtHTT protein is assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • level of wtHTT protein is assessed about 28 days after a last dose of a set of doses.
  • level of wtHTT protein is assessed about 56 days after a last dose of 113 of 265 12842751v1 Attorney Docket No.: 2010581-1510 a set of doses. In some embodiments, level of wtHTT protein is assessed about 84 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF if assessed about 28 days after a last dose of a set of doses. In some embodiments, level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF if assessed about 56 days after a last dose of a set of doses.
  • level of wtHTT protein in CSF of a subject is increased compared to a reference level of wtHTT protein in CSF if assessed about 84 days after a last dose of a set of doses.
  • a reference wtHTT protein level is or comprises a baseline level.
  • ventricular volume of a subject after one or more WVE-003 doses is comparable to a reference ventricular volume.
  • ventricular volume is assessed by MRI.
  • ventricular volume is assessed by MRI about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses. In some embodiments, ventricular volume is assessed by MRI. In some embodiments, ventricular volume is assessed by MRI about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, ventricular volume is assessed by MRI about 28 days after a last dose of a set of doses. In some embodiments, ventricular volume is assessed by MRI about 56 days after a last dose of a set of doses.
  • ventricular volume is assessed by MRI about 84 days after a last dose of a set of doses.
  • a reference ventricular volume is a baseline ventricular volume.
  • TMS of a subject is reduced after one or more WVE-003 doses compared to a reference TMS.
  • TMS of a subject is reduced after a last dose of a set of doses.
  • a reference TMS is a baseline TMS.
  • a dosing regimen comprises a set of two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) doses of WVE-003.
  • a dosing regimen comprises three or more doses of WVE-003. In some embodiments, a dosing regimen comprises a set of two or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form. In some embodiments, a dosing regimen comprises a set of three or more doses of WVE-003, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about every 8 weeks or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein the set of doses are administered or delivered about every 8 weeks or less frequently. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about every 8 weeks. In some embodiments, a dosing regimen comprises a set of three or more 114 of 265 12842751v1 Attorney Docket No.: 2010581-1510 doses, wherein the set of doses are administered or delivered about every 8 weeks. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about every 12 weeks or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein the set of doses are administered or delivered about every 12 weeks or less frequently. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about every 12 weeks. In some embodiments, a dosing regimen comprises a set of three or more doses, wherein the set of doses are administered or delivered about every 12 weeks. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about quarterly or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein the set of doses are administered or delivered about quarterly or less frequently. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein the set of doses are administered or delivered about quarterly. In some embodiments, a dosing regimen comprises a set of three or more doses, wherein the set of doses are administered or delivered about quarterly. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks or less frequently.
  • a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 8 weeks.
  • a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks or less frequently.
  • a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about every 12 weeks. In some embodiments, a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about quarterly or less frequently.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are 115 of 265 12842751v1 Attorney Docket No.: 2010581-1510 administered or delivered about quarterly or less frequently.
  • a dosing regimen comprises a set of two or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about quarterly.
  • a dosing regimen comprises a set of three or more doses, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form and the set of doses are administered or delivered about quarterly. [0500] In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein.
  • a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein if assessed about 28, 56, or 84 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein if assessed about 28 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein if assessed about 56 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects about 30% or more reduction in level of mHTT protein in CSF compared to a reference level of mHTT protein if assessed about 84 days after a last dose of a set of doses.
  • a reference level of mHTT protein is or comprises a baseline level of mHTT protein in CSF of the population of subjects.
  • a reference level of mHTT protein is or comprises a baseline level of mHTT protein in CSF of a reference population.
  • subjects of a reference population each independently receive a dose of placebo for each dose of WVE-003.
  • a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF. In some embodiments, a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF if assessed about 28 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF if assessed about 56 days 116 of 265 12842751v1 Attorney Docket No.: 2010581-1510 after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve about 30%, 35%, 40%, 41%, 42%, 43%, 44%, 45%, 46% or more reduction of level of mHTT protein in CSF if assessed about 84 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve about 46% reduction in level of mHTT protein in CSF if assessed about 56 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve about 46% reduction in level of mHTT protein in CSF if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three. In some embodiments, a dosing regimen is demonstrated to achieve about 44% reduction in level of mHTT protein in CSF if assessed about 84 days after a last dose of a set of doses, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve about 46% reduction in level of mHTT protein in CSF if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks. In some embodiments, a dosing regimen is demonstrated to achieve about 44% reduction in level of mHTT protein in CSF if assessed about 84 days after a last dose of a set of doses, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF. In some embodiments, a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF if assessed about 28 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF if assessed about 56 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve a level of wtHTT protein in CSF that is not reduced as compared to a reference level of wtHTT protein in CSF if assessed about 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 28 days after a last dose of a set of doses as compared to a placebo.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 56 days after a last dose of a set of doses as compared to a placebo. In some embodiments, a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 84 days after a last dose of a set of doses as compared to a placebo. In some embodiments, a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 28 days after a last dose of a set of doses as compared to a placebo, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 56 days after a last dose of a set of doses as compared to a placebo, wherein 117 of 265 12842751v1 Attorney Docket No.: 2010581-1510 the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 84 days after a last dose of a set of doses as compared to a placebo, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 28 days after a last dose of a set of doses as compared to a placebo, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 56 days after a last dose of a set of doses as compared to a placebo, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • a dosing regimen is demonstrated to achieve no wtHTT protein reduction in CSF 84 days after a last dose of a set of doses as compared to a placebo, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • a dosing regimen is demonstrated to achieve in a population of subjects no significant ventricular volume change compared to baseline ventricular volume of the population.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 28 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change if assessed about 28 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 56 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change if assessed about 56 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects 118 of 265 12842751v1 Attorney Docket No.: 2010581-1510 ventricular volume change that is comparable to a reference ventricular volume change if assessed about 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is no larger than a reference ventricular volume change if assessed about 84 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve in a population of subjects ventricular volume change that is comparable to a reference ventricular volume change if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • a reference ventricular volume change is a ventricular volume change of a reference population.
  • subjects of a reference population each independently receive a dose of placebo for each dose of WVE-003.
  • ventricular volume is assessed by MRI.
  • a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects.
  • a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 28, 56, or 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 28 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 84 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • subjects of a reference population each independently receive a dose of placebo for each dose of WVE-003.
  • caudate atrophy is assessed by MRI.
  • a dosing regimen is demonstrated to achieve in a population of subjects 119 of 265 12842751v1 Attorney Docket No.: 2010581-1510 TMS reduction compared to placebo in a reference population of subjects.
  • a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 or more days or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 28, 56, or 84 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 28 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses. In some embodiments, a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 84 days after a last dose of a set of doses.
  • a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three.
  • a dosing regimen is demonstrated to achieve in a population of subjects TMS reduction compared to a placebo in a reference population of subjects if assessed about 56 days after a last dose of a set of doses, wherein the number of doses in the set is three and the three doses are administered about every 8 weeks.
  • subjects of a reference population each independently receive a dose of placebo for each dose of WVE-003.
  • a last dose is a first dose. In some embodiments, a last dose is a second dose. In some embodiments, a last dose is a third dose. [0507] In some embodiments, a subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene. In some embodiments, a subject is HD-ISS Stage 0, 1, 2, or 3. In some embodiments, a subject is HD-ISS Stage 3. In some embodiments, a subject is HD-ISS Stage 0, 1, or 2. In some embodiments, a subject is HD-ISS Stage 1 or 2.
  • a subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 0, 1, 2, or 3. In some embodiments, a subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 3. In some embodiments, a subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 0, 1, or 2. In some embodiments, a subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 1 or 2.
  • one or more or all subjects have the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene.
  • one or more or all subjects are HD- ISS Stage 0, 1, 2, or 3.
  • one or more or all subjects are HD-ISS Stage 3.
  • one or more or all subjects are HD-ISS Stage 0, 1, or 2.
  • one or more or all subjects are HD-ISS Stage 1 or 2.
  • one or more or all subjects have the A variant of 120 of 265 12842751v1 Attorney Docket No.: 2010581-1510 rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and are HD-ISS Stage 0, 1, 2, or 3. In some embodiments, one or more or all subjects have the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and are HD-ISS Stage 3. In some embodiments, one or more or all subjects have the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and are HD-ISS Stage 0, 1, or 2.
  • one or more or all subjects have the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and are HD-ISS Stage 1 or 2.
  • one or more or all subjects of the population do not manifest Huntington’s disease.
  • one or more or all subjects of the population independently suffer from Huntington’s disease.
  • “about” is ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 6%, ⁇ 7%, ⁇ 8%, ⁇ 9%, or ⁇ 10% of a value.
  • the present disclosure provides a method for treating or preventing Huntington’s disease, wherein the method comprises the step of administering to a subject an effective amount of a HTT oligonucleotide or composition thereof described herein (e.g., WVE-003).
  • a HTT transcript is of Huntingtin gene or a variant thereof.
  • HTT oligonucleotides can elicit pro-inflammatory responses.
  • the present disclosure provides compositions and methods for reducing inflammation.
  • the present disclosure provides compositions and methods for reducing pro-inflammatory responses. In some embodiments, the present disclosure provides methods for reducing injection site inflammation using provided compositions. In some embodiments, the present disclosure provides methods for reducing drug-induced vascular injury using provided compositions.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT 121 of 265 12842751v1 Attorney Docket No.: 2010581-1510 transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 90 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT 123 of 265 12842751v1 Attorney Docket No.: 2010581-1510 transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 90 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 60 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 120 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 30 mg +5%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 90 mg +5%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 120 mg +5%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 150 mg +5%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg +5%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 30 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 60 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT 126 of 265 12842751v1 Attorney Docket No.: 2010581-1510 gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 90 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 120 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 150 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg +10%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 30 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 60 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 90 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) 127 of 265 12842751v1 Attorney Docket No.: 2010581-1510 at a dose of 120 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 150 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg +15%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 30 mg +20%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 60 mg +20%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 90 mg +25%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 120 mg +25%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 150 mg +25%, such that progression of Huntington’s disease in the subject is delayed, and/or the 128 of 265 12842751v1 Attorney Docket No.: 2010581-1510 onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg +25%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 30 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 60 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 90 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 120 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 150 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the present disclosure pertains to: A method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene, wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 168 mg +30%, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • the subject is administered a steroid prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered a steroid at least about one month prior to the first dose of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is on a steroid regimen for at least about one month prior to the first dose of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is administered an oral corticosteroid for at least about 24 months prior to the first dose of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is administered hydrocortisone and/or acetaminophen within 24 hours of administration of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 2 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 4 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 8 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 12 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 16 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 32 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 48 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 50 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 60 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 70 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 80 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 90 months.
  • the subject is administered a HTT oligonucleotide or a HTT oligonucleotide composition approximately monthly for at least about 100 months.
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline, in the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the Huntingtin protein production is measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, or immunohistochemical detection.
  • RT-PCR reverse transcription polymerase chain reaction
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, such that disease progression in the subject is delayed (e.g., as measured by any appropriate technique described herein or known in the art), thereby treating the subject, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a HTT oligonucleotide or a HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline in the subject as measured by any method known in the art and/or described herein, wherein the HTT oligonucleotide or HTT oligonucleotide is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the method further comprises the step of administering to the subject a corticosteroid.
  • the corticosteroid is Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, or Prednisone.
  • the corticosteroid is administered prior to, in conjunction with, or subsequent to administration of a HTT oligonucleotide or a HTT oligonucleotide composition.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with 131 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 90 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with 132 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 90 mg approximately monthly, such that disease 133 of 265 12842751v1 Attorney Docket No.: 2010581-1510 progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the intrathecal administration is a bolus.
  • the subject is administered a steroid prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered a steroid at least about one month prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is on a steroid regimen for at least about one month prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered an oral corticosteroid for at least about 24 months prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered hydrocortisone and/or acetaminophen within 24 hours of administration of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered a chirally controlled HTT oligonucleotide 134 of 265 12842751v1 Attorney Docket No.: 2010581-1510 composition approximately monthly for at least about 2 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 4 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 8 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 12 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 16 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 32 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 48 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 50 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 60 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 70 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 80 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 90 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 100 months.
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline, in the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the Huntingtin protein production is measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, or immunohistochemical detection.
  • RT-PCR reverse transcription polymerase chain reaction
  • the present disclosure pertains to: A method for treating a subject with 135 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, such that disease progression in the subject is delayed as measured by a protocol described herein (e.g., in the Examples), thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline in the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating a decrease in the level, expression and/or activity of a mHTT transcript.
  • the intrathecal administration is a bolus.
  • the method further comprises the step of administering to the subject a corticosteroid.
  • the corticosteroid is Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, or Prednisone.
  • the corticosteroid is administered prior to, in conjunction with, or subsequent to administration of a chirally controlled HTT oligonucleotide composition.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the 136 of 265 12842751v1 Attorney Docket No.: 2010581-1510 level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to 168 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising the step of administering to the subject WVE-003 (or a 137 of 265 12842751v1 Attorney Docket No.: 2010581-1510 salt form thereof) at a dose of about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of 30, 60, 90, 120, 150, or 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg approximately monthly, such that disease progression in the 138 of 265 12842751v1 Attorney Docket No.: 2010581-1510 subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject.
  • WVE-003 or a salt form thereof
  • the subject is administered a steroid prior to the first dose of WVE-003.
  • the subject is administered a steroid at least about one month prior to the first dose of WVE-003.
  • the subject is on a steroid regimen for at least about one month prior to the first dose of WVE-003.
  • the subject is administered an oral corticosteroid for at least about 24 months prior to the first dose of WVE-003.
  • the subject is administered hydrocortisone and/or acetaminophen within 24 hours of administration of WVE-003.
  • the subject is administered WVE-003 approximately monthly for at least about 2 months.
  • the subject is administered WVE-003 approximately monthly for at least about 4 months.
  • the subject is administered WVE-003 approximately monthly for at least about 8 months.
  • the subject is administered WVE-003 approximately monthly for at least about 12 months.
  • the subject is administered WVE-003 approximately monthly for at least about 16 months.
  • the subject is administered WVE-003 approximately monthly for at least about 32 months.
  • the subject is administered WVE-003 approximately monthly for at least about 48 months.
  • the subject is administered WVE-003 approximately monthly for at least about 50 months.
  • the subject is administered WVE-003 approximately monthly for at least about 60 months.
  • the subject is administered WVE-003 approximately monthly for at least about 70 months.
  • the subject is administered WVE-003 approximately monthly for at least about 80 months.
  • the subject is administered WVE-003 approximately monthly for at least about 90 months.
  • the subject is administered WVE-003 approximately monthly for at least about 100 months.
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of mHTT, comprising intrathecally administering to the subject WVE-003 (or a salt form thereof) at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline, in the subject.
  • the Huntingtin protein production is measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, or immunohistochemical detection.
  • the method further comprises the step of administering to the subject a corticosteroid.
  • the corticosteroid is Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, or Prednisone.
  • the corticosteroid is administered prior to, in conjunction with, or subsequent to administration of WVE-003.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT 140 of 265 12842751v1 Attorney Docket No.: 2010581-1510 oligonucleotide composition at a dose of 30, 60, 90, 120, 150, or 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 90 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a 141 of 265 12842751v1 Attorney Docket No.: 2010581-1510 mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising the step of administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 90 mg, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 90 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with 143 of 265 12842751v1 Attorney Docket No.: 2010581-1510 Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 30 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 60 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a 144 of 265 12842751v1 Attorney Docket No.: 2010581-1510 mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 120 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 150 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the present disclosure pertains to: A method for treating a subject with Huntington’s disease who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of about 168 mg approximately monthly, such that disease progression in the subject is delayed, thereby treating the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the subject is administered a steroid prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered a steroid at least about one month prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is on a steroid regimen for at least about one month prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered an oral corticosteroid for at least about 24 months prior to the first dose of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered hydrocortisone and/or acetaminophen within 24 hours of administration of a chirally controlled HTT oligonucleotide composition.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 2 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 4 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 8 months.
  • the subject is administered a chirally controlled HTT oligonucleotide 145 of 265 12842751v1 Attorney Docket No.: 2010581-1510 composition approximately monthly for at least about 12 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 16 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 32 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 48 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 50 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 60 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 70 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 80 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 90 months.
  • the subject is administered a chirally controlled HTT oligonucleotide composition approximately monthly for at least about 100 months.
  • the present disclosure pertains to: A method for reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease in a subject with Huntington’s disease in need thereof who has a mutation of the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript, comprising intrathecally administering to the subject a chirally controlled HTT oligonucleotide composition at a dose of 10 to about 168 mg approximately monthly, thereby reducing the severity of and/or delaying the onset of at least one symptom of Huntington’s disease relative to baseline, in the subject, wherein the chirally controlled HTT oligonucleotide composition is capable of mediating an allele-specific decrease in the level, expression and/or activity of a mHTT transcript.
  • the Huntingtin protein production is measured by reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, or immunohistochemical detection.
  • the method further comprises the step of administering to the subject a corticosteroid.
  • the corticosteroid is Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, or Prednisone.
  • the corticosteroid is administered prior to, in conjunction with, or subsequent to administration of a chirally controlled HTT oligonucleotide composition.
  • the method further comprises the step of confirming that the subject has a 146 of 265 12842751v1 Attorney Docket No.: 2010581-1510 mutation in the HTT gene that is amenable to allele-specific knockdown of a mutant HTT transcript.
  • the present disclosure provides methods of use of a composition comprising any HTT oligonucleotide disclosed herein. In some embodiments, the present disclosure provides methods of use of a composition comprising any chirally controlled HTT oligonucleotide disclosed herein.
  • the present disclosure provides methods of use of a composition comprising a HTT oligonucleotide disclosed herein which is capable of mediating allele-specific knockdown of mutant HTT. In some embodiments, the present disclosure provides methods of use of a composition comprising a HTT oligonucleotide disclosed herein which is capable of mediating allele-specific knockdown of a mutant HTT transcript. In some embodiments, the present disclosure provides methods of use of a composition comprising a HTT oligonucleotide disclosed herein which is capable of mediating allele-specific knockdown of a mutant HTT transcript.
  • the present disclosure provides methods of use of a composition comprising a HTT oligonucleotide(s) disclosed herein which is capable of mediating allele-specific knockdown of mutant HTT transcript.
  • a composition is a chirally controlled HTT oligonucleotide composition.
  • the HTT oligonucleotide is WVE-003.
  • the present disclosure provides a pharmaceutical composition comprising a HTT oligonucleotide or a HTT oligonucleotide composition of the present disclosure (e.g., WVE-003 ) and a pharmaceutically acceptable carrier (including but not limited to, a pharmaceutically acceptable salt).
  • the present disclosure provides a method for allele-specific knockdown of a target HTT transcript, comprising the step of administering a HTT oligonucleotide composition of the present disclosure.
  • the present disclosure provides a method for reducing level of a HTT transcript or a product thereof, comprising the step of administering a HTT oligonucleotide composition of the present disclosure.
  • a method for treating Huntington’s disease comprising the step of administering to a subject susceptible thereto or suffering therefrom a composition described in the present disclosure.
  • the present disclosure provides a method for treating Huntington’s disease, comprising the step of administering to a subject susceptible thereto or suffering therefrom a composition comprising any HTT oligonucleotide disclosed herein.
  • the present disclosure provides a method for treating Huntington’s disease, comprising (a) administering to a subject susceptible thereto or suffering therefrom a composition comprising any HTT oligonucleotide disclosed herein, and (b) administering to the subject additional treatment which is capable of preventing, treating, ameliorating or slowing the progress of Huntington’s disease.
  • aCSF artificial cerebrospinal fluid
  • aPTT activated partial thromboplastin time
  • ASO antisense oligonucleotide
  • AUC area under the plasma concentration-time curve 147 of 265 12842751v1
  • ASO antisense oligonucleotide
  • AUC0-24 area under the curve from time 0 to 24 hours
  • AUClast area under the curve from 0 to time of the last quantifiable concentration
  • BLQ BLOQ: below the limit of quantification
  • BP British Pharmacopeia
  • BUN blood urea nitrogen
  • C variant wild-type variant of SNP1
  • C0 extrapolated initial concentration at time 0
  • CAG cytosine-adenine-guanine
  • Cmax maximum observed concentration
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • CYP cytochrome P450 DNA: deoxyribonucleic acid
  • ECG electrocardiogram
  • GAPDH Female FOB:
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, such that progression of Huntington’s disease in the subject 149 of 265 12842751v1 Attorney Docket No.: 2010581-1510 is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 2.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 3.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 4.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 5.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 6.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 7.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 160 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a 150 of 265 12842751v1 Attorney Docket No.: 2010581-1510 symptom of Huntington’s disease is reduced.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 12.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 13.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 14.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 160 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 15.
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • WVE-003 or a salt form thereof
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg. 17.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 60 mg. 18.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene wherein the method comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 90 mg. 19.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 120 mg. 20.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 150 mg. 21.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 160 mg. 22.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 168 mg. 23.
  • a method for treating Huntington’s disease comprising administering to a subject suffering therefrom WVE-003 (or a salt form thereof), wherein WVE-003 is administered at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, and wherein the subject has a HTT allele that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE- 003. 24.
  • a method for treating Huntington’s disease comprising administering to a subject suffering therefrom a pharmaceutical composition that comprises or delivers WVE-003 (or a salt form thereof), wherein WVE-003 is administered at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 152 of 265 12842751v1 Attorney Docket No.: 2010581-1510 mg, or about 168 mg, and wherein the subject has a HTT allele that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE-003. 25.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to have a genetic sequence that is the same or fully complementary to the base sequence of WVE- 003. 26. A method, comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to have a genetic sequence that comprises a sequence that is the same or fully complementary to the base sequence of WVE-003 and a sequence that is or encodes an expanded CAG repeats. 27.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to have a genetic sequence that encodes a transcript that comprises an expanded CAG repeat in HTT and is fully complementary to the base sequence of WVE-003.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to express a HTT transcript that comprises an expanded CAG repeat and is fully complementary to the base sequence of WVE-003.
  • 29 The method of any one of Embodiments 25-28, wherein the subject is determined to have a genetic sequence or transcript that is not the same or fully complementary to the base sequence of WVE-003 at rs362273.
  • the method of any one of Embodiments 25-37 comprising administering multiple doses monthly. 52. The method of any one of Embodiments 25-37, comprising administering multiple doses every two months. 53. The method of any one of Embodiments 25-37, comprising administering multiple doses every 3, 4, 5, 6 or more months. 54. The method of any one of Embodiments 25-53, wherein expression of mutant HTT is reduced. 55. The method of any one of Embodiments 25-54, wherein mutant HTT protein level is reduced. 56. The method of any one of Embodiments 54-55, wherein the reduction is about 10% or more. 57. The method of any one of Embodiments 54-55, wherein the reduction is about 12% or more. 58.
  • the method of any one of Embodiments 54-55, wherein the reduction is about 15% or more.
  • the method of any one of Embodiments 54-55, wherein the reduction is about 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more.
  • the method of any one of Embodiments 54-59, wherein the reduction is assessed for an individual subject.
  • the method of any one of Embodiments 54-59, wherein the reduction is assessed for a population of 154 of 265 12842751v1 Attorney Docket No.: 2010581-1510 subjects. 62.
  • Embodiment 61 wherein the reduction is assessed for a population of subjects, wherein the population size is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000 or more subjects.
  • 63. The method of Embodiment 60 or 61, wherein subjects in the population receive the same dosage regimen.
  • 65. The method of any one of Embodiments 54-64, wherein one or more cerebrospinal fluid samples are utilized for reduction assessment.
  • 66. The method of any one of Embodiments 54-65, wherein wild-type HTT transcript level is not significantly reduced. 67.
  • Embodiments 54-70 The method of any one of Embodiments 54-70, wherein assessment is performed after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, or about 3, 4, 5, 6, 7, or 8 weeks, or about 3, 4, 5, or 6 or more months after administration of a dose and before a next dose, if any, is administered.
  • 72. The method of any one of Embodiments 54-71, wherein assessment is performed after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses are administered.
  • 73 The method of any one of Embodiments 54-72, wherein onset of and/or severity of a symptom of Huntington’s disease in a subject is delayed and/or reduced. 74.
  • the method further comprises the step of confirming that the subject has a mutation in the HTT gene that is amenable to an allele-specific knockdown 156 of 265 12842751v1 Attorney Docket No.: 2010581-1510 of the mutant HTT gene or a gene product thereof transcript.
  • WVE-003 is administered in a salt form.
  • WVE-003 is administered in a sodium salt form.
  • WVE-003 is formulated as a liquid formulation. 99.
  • WVE-003 is formulated as a liquid formulation, wherein the liquid formulation comprises WVE-003, sodium chloride, and water.
  • WVE-003 is formulated as a liquid formulation, wherein the liquid formulation is reconstituted from a lyophilized preparation.
  • 101 The method of any one of the previous Embodiments, wherein the level, expression and/or activity of a mHTT transcript or gene product thereof is reduced by at least about 5%.
  • the amount of WVE- 003 includes the amount of one or more pharmaceutically acceptable salt forms, each of which is independently 157 of 265 12842751v1 Attorney Docket No.: 2010581-1510 converted to the amount of the acid form.
  • a method for treating Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp
  • a method for preventing Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents
  • a method comprising administering or delivering to a subject WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE- 158 of 265 12842751v1 Attorney Docket No.: 2010581-1510 003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OM
  • a method for decreasing the activity, expression, and/or level of a mutant HTT gene or its gene product in a subject comprising administering or delivering to the subject WVE-003 at a dose equivalent to about 10- 200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE- 003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’
  • a method for preferential knockdown of a repeat expansion-containing HTT RNA transcript relative to a non-repeat expansion-containing HTT RNA transcript in a subject comprising administering or delivering to the subject WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo
  • a method for reducing level of a HTT transcript comprising CAG repeat expansion in a subject comprising administering or delivering to the subject WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a
  • a method for reducing level of a product of a HTT transcript comprising CAG repeat expansion in a subject comprising administering or delivering to the subject WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form, wherein WVE-003 is: mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification
  • each dose of WVE-003 is independently administered in a pharmaceutical composition comprising WVE-003 and a pharmaceutically acceptable carrier.
  • each dose of WVE-003 is independently administered in a pharmaceutical composition comprising a WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier. 161 of 265 12842751v1 Attorney Docket No.: 2010581-1510 135.
  • each dose of WVE-003 is independently administered in a pharmaceutical composition consisting of WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier.
  • each dose of WVE-003 is independently administered in a pharmaceutical composition consisting of WVE-003 pentadecasodium salt dissolved in a pharmaceutically acceptable carrier.
  • a method for treating Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 pentadecasodium salt: 12842751v1 Attorney Docket No.: 2010581-1510 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10- 170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 138.
  • a method for preventing Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10- 200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 139.
  • a method comprising administering or delivering to a subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 140.
  • a method for decreasing the activity, expression, and/or level of a mutant HTT gene or its gene product in a subject comprising administering or delivering to the subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 141.
  • a method for preferential knockdown of a repeat expansion-containing HTT RNA transcript relative to a non-repeat expansion-containing HTT RNA transcript in a subject comprising administering or delivering to the subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 142.
  • a method for reducing level of a HTT transcript comprising CAG repeat expansion in a subject comprising administering or delivering to the subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form.
  • 143 e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about
  • a method for reducing level of a product of a HTT transcript comprising CAG repeat expansion in a subject comprising administering or delivering to the subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, 163 of 265 12842751v1 Attorney Docket No.: 2010581-1510 about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 144.
  • Embodiment 143 wherein the product is a polypeptide.
  • 146 The method of any one of Embodiments 137-145, wherein two or more doses, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more doses are administered.
  • 147 The method of any one of Embodiments 137-146, wherein a dose of WVE-003 pentadecasodium salt is administered in a pharmaceutical composition comprising WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier.
  • each dose of WVE-003 pentadecasodium salt is independently administered in a pharmaceutical composition consisting of WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier.
  • each dose of WVE-003 pentadecasodium salt is independently administered in a pharmaceutical composition consisting of WVE-003 pentadecasodium salt dissolved in a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is aCSF.
  • a dose is equivalent to about 10 mg WVE-003 free acid form.
  • a dose is equivalent to about 20 mg WVE-003 free acid form.
  • a dose is equivalent to about 30 mg WVE-003 free acid form.
  • a dose is equivalent to about 40 mg WVE-003 free acid form.
  • a dose is equivalent to about 100 mg WVE-003 free acid form. 164. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 110 mg WVE-003 free acid form. 165. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 120 mg WVE-003 free acid form. 166. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 130 mg WVE-003 free acid form. 167. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 140 mg WVE-003 free acid form. 168.
  • a dose is equivalent to about 150 mg WVE-003 free acid form. 169. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 160 mg WVE-003 free acid form. 170. The method of any one of the preceding Embodiments, wherein a dose is equivalent to about 170 mg WVE-003 free acid form. 171. The method of any one of Embodiments 114-153, wherein each dose is independently equivalent to about 10 mg WVE-003 free acid form. 172. The method of any one of Embodiments 114-153, wherein each dose is independently equivalent to about 20 mg WVE-003 free acid form. 173.
  • the method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every two months. 200. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every two months or less frequently. 201. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every three months. 202. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about every four months. 203. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about quarterly or less frequently. 204. The method of any one of the preceding Embodiments, wherein two or more consecutive doses are administered about quarterly.
  • the method of any one of the preceding Embodiments, wherein the A variant of rs362273 is on the same allele as the expanded CAG repeat region in a HTT gene. 219.
  • the expanded CAG repeat region comprises 40 or more CAG repeats. 221.
  • level of mHTT transcript in cerebrospinal fluid is reduced by about 10%, 20%, 30%, 40%, 50% or more about or after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more weeks after a first dose. 222.
  • level of mHTT polypeptide in cerebrospinal fluid is reduced by about 10%, 20%, 30%, 40%, 50% or more about or after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more weeks after a first dose. 223.
  • 224 The method of any one of the preceding Embodiments, wherein the level is reduced by about 20% or more.
  • 225 The method of any one of the preceding Embodiments, wherein the level is reduced by about 30% or more. 226.
  • the composition has a purity of about 80%-90%. 249.
  • the method of any one of the preceding Embodiments, wherein the composition has a purity of about 82% or more. 250.
  • the method of any one of the preceding Embodiments, wherein the composition has a purity of about 84% or more. 251.
  • the method of any one of the preceding Embodiments, wherein the composition has a purity of about 85% or more. 252.
  • the method of any one of the preceding Embodiments, wherein the composition has a purity of about 86% or more. 253.
  • the method of any one of Embodiments 260-273, wherein the impurities are measured by an IP-RP- UPLC method for purity as described herein. 275.
  • stereochemical purity of WVE-003 is about 83% or more. 277.
  • stereochemical purity of WVE-003 is about 80%-85%. 278.
  • stereochemical purity is assessed by dimer modeling. 279.
  • the amount of WVE-003 is measured by UV at 260 nm and 25.0 OD/mg. 280.
  • a pharmaceutical composition is characterized by one or more methods described herein. 294.
  • the method of any one of the preceding Embodiments, wherein a pharmaceutical composition is released by one or more methods described herein. 295.
  • the method of any one of the preceding Embodiments, wherein a pharmaceutical composition is stored by one or more methods described herein. 296.
  • the method of any one of the preceding Embodiments, wherein WVE-003 is administered intrathecally. 297.
  • the method of any one of the preceding Embodiments, wherein WVE-003 is administered by direct lumbar injection. 298.
  • the method of any one of the preceding Embodiments, wherein the subject improves in functional assessments.
  • composition of Embodiment 311, wherein a form of WVE-003 in the composition is a pharmaceutically acceptable salt form.
  • composition of any one of Embodiments 311-312, wherein each form of WVE-003 in the composition is independently a salt form.
  • composition of any one of Embodiments 311-313, wherein each form of WVE-003 in the composition is independently a pharmaceutically acceptable salt form.
  • 315 The composition of any one of Embodiments 311-314, wherein a form of WVE-003 in the composition is WVE-003 pentadecasodium salt. 316.
  • the composition of any one of the Embodiments 311-316, wherein the composition is a drug substance.
  • composition of any one of Embodiments 311-316, wherein the composition is a drug product. 321.
  • composition is a liquid composition wherein WVE-003 is dissolved.
  • composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is or comprises artificial cerebrospinal fluid (aCSF).
  • aCSF artificial cerebrospinal fluid
  • WVE-003 in the composition is equivalent to about 5 mg WVE-003 free acid form. 331.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 10 mg WVE-003 free acid form.
  • WVE-003 in the composition is equivalent to about 20 mg WVE-003 free acid form.
  • 333. The composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 30 mg WVE-003 free acid form.
  • 334. The composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 40 mg WVE-003 free acid form. 335.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 50 mg WVE-003 free acid form.
  • WVE-003 in the composition is equivalent to about 60 mg WVE-003 free acid form.
  • WVE-003 in the composition is equivalent to about 70 mg WVE-003 free acid form.
  • WVE-003 in the composition is equivalent to about 80 mg WVE-003 free acid form. 339.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 90 mg WVE-003 free acid form.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 100 mg WVE-003 free acid form.
  • WVE-003 in the composition is equivalent to about 110 mg WVE-003 free acid form.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 120 mg WVE-003 free acid form. 343.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 130 mg WVE-003 free acid form. 344.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 140 mg WVE-003 free acid form. 345.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is 174 of 265 12842751v1 Attorney Docket No.: 2010581-1510 equivalent to about 150 mg WVE-003 free acid form.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 160 mg WVE-003 free acid form. 347.
  • composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 170 mg WVE-003 free acid form.
  • composition of any one of the preceding Embodiments, wherein the composition is packaged into a vial.
  • composition of any one of the preceding Embodiments, wherein the composition is reconstituted and diluted in artificial cerebrospinal fluid (aCSF).
  • aCSF artificial cerebrospinal fluid
  • a composition, which composition is WVE-003 dissolved in a pharmaceutically acceptable carrier, wherein the amount of WVE-003 in the composition is equivalent to about 30 mg WVE-003 free acid form. 351.
  • composition of any one of the preceding Embodiments, wherein the composition has a purity of about 70%-90%. 356.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 80%-90%. 357.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 80% or more. 358.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 81% or more. 359.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 82% or more. 360.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 83% or more. 361.
  • composition of any one of the preceding Embodiments, wherein the composition has a purity of about 84% or more. 362.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 85% or more. 175 of 265 12842751v1 Attorney Docket No.: 2010581-1510 363.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 86% or more. 364.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 87% or more. 365.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 88% or more. 366.
  • composition of any one of the preceding Embodiments, wherein the composition has a purity of about 89% or more. 367.
  • the composition of any one of the preceding Embodiments, wherein the composition has a purity of about 90% or more. 368.
  • the composition of any one of Embodiments 349-367, wherein the purity is measured by IP-RP-UPLC using area % at 260 nm. 369.
  • the composition of any one of Embodiments 349-369, wherein the purity is measured by an IP-RP- UPLC method for purity as described herein. 371.
  • composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about 10%-30%. 372. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about 10%-20%. 373. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 20%. 374. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 19%. 375. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 18%. 376.
  • composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 17%. 377.
  • the composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 16%. 378.
  • the composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 15%. 379.
  • the composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 14%. 380.
  • the composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 13%.
  • composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 12%. 382. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 11%. 383. The composition of any one of the preceding Embodiments, wherein impurities in the composition are no more than about or about 10%. 384. The composition of any one of Embodiments 371-383, wherein the impurities are measured by IP-RP- UPLC using area % at 260 nm. 385.
  • the composition of any one of the preceding Embodiments, wherein stereochemical purity of WVE- 003 is about 80% or more.
  • stereochemical purity of WVE- 003 is about 83% or more. 389.
  • composition of any one of the preceding Embodiments, wherein stereochemical purity of WVE- 003 is about 80%-85%. 390.
  • the composition of any one of the preceding Embodiments, wherein the amount of WVE-003 is measured by UV at 260 nm. 392.
  • the composition of any one of the preceding Embodiments, wherein the amount of WVE-003 is measured by UV at 260 nm and 25.0 OD/mg. 393.
  • the composition of any one of the preceding Embodiments, wherein the WVE-003 drug substance in the composition is manufactured by a process described herein. 394.
  • composition of any one of the preceding Embodiments, wherein the WVE-003 drug substance in the composition is characterized by one or more methods described herein. 395.
  • the composition of any one of the preceding Embodiments, wherein the WVE-003 drug substance in the composition is released by one or more methods described herein. 396.
  • the composition of any one of the preceding Embodiments, wherein the WVE-003 drug substance is stored by one or more methods described herein. 397.
  • the composition of any one of Embodiments 393-396, wherein the WVE-003 drug substance is pentadecasodium salt. 398.
  • the composition of any one of the preceding Embodiments, wherein the composition is a WVE-003 drug product.
  • composition of any one of the preceding Embodiments, wherein the composition is a WVE-003 drug product which is lyophilized WVE-003 pentadecasodium salt. 400.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 drug product is manufactured by a process described herein.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 drug product is characterized by one or more methods described herein. 402.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 drug product is released by one or more methods described herein. 403.
  • composition of any one of the preceding Embodiments, wherein WVE-003 drug product is stored by one or more methods described herein. 404.
  • the composition of any one of the preceding Embodiments, wherein the composition is manufactured by a process described herein. 405.
  • the composition of any one of the preceding Embodiments, wherein a pharmaceutical composition is characterized by one or more methods described herein. 406.
  • the composition of any one of the preceding Embodiments, wherein a pharmaceutical composition is released by one or more methods described herein. 407.
  • the composition of any one of the preceding Embodiments, wherein a pharmaceutical composition is stored by one or more methods described herein. 408.
  • the composition of any one of the preceding Embodiments, wherein about is ⁇ 1%. 409.
  • composition of any one of the preceding Embodiments, wherein about is ⁇ 2%. 410.
  • the composition of any one of the preceding Embodiments, wherein about is ⁇ 3%. 411.
  • the composition of any one of the preceding Embodiments, wherein about is ⁇ 4%. 412.
  • the composition of any one of the preceding Embodiments, wherein about is ⁇ 5%. 413.
  • the composition of any one of the preceding Embodiments, wherein about is ⁇ 8%. 416.
  • a container containing WVE-003 as described in any one of the preceding Embodiments, wherein the amount of WVE-003 in the contain is equivalent to about 30 mg WVE-003 free acid form. 422.
  • a device comprising or for delivering a composition of any one of the preceding Embodiments. 428.
  • a syringe comprising or for delivering a composition of any one of the preceding Embodiments. 429.
  • Embodiment 434 comprising utilizing IP-RP-UPLC to assess purity and/or impurities in the manufactured WVE-003 composition and release the preparation if the purity and/or impurities meet certain criteria.
  • 436 The method of any one of Embodiments 434-435, wherein the composition is a drug substance. 437.
  • a method for releasing a WVE-003 preparation comprising utilizing IP-RP-UPLC to assess purity and/or impurities in the WVE-003 preparation and release the preparation if the purity and/or impurities meet certain criteria. 439.
  • a method for treating a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, such that progression of Huntington’s disease in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced.
  • WVE-003 or a salt form thereof
  • a method for treating Huntington’s disease in a subject who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, such that disease progression in the subject is delayed, and/or the onset of Huntington’s disease is delayed, and/or the severity of a symptom of Huntington’s disease is reduced. 451.
  • a method of delaying the onset of and/or reducing the severity of a symptom of Huntington’s disease in a subject with Huntington’s disease who has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene comprises the step of administering to the subject WVE-003 (or a salt form thereof) at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg,. 452.
  • a method for treating Huntington’s disease comprising administering to a subject suffering therefrom WVE-003 (or a salt form thereof), wherein WVE-003 is administered at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, and wherein the subject has a HTT allele that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE- 003. 453.
  • a method for treating Huntington’s disease comprising administering to a subject suffering therefrom a pharmaceutical composition that comprises or delivers WVE-003 (or a salt form thereof), wherein WVE-003 is administered at a dose of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 160 mg, or about 168 mg, and wherein the subject has a HTT allele that comprises an expanded CAG repeat region and is fully complementary to the base sequence of WVE-003. 454.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to have a genetic sequence that is the same or fully complementary to the base sequence of WVE- 180 of 265 12842751v1 Attorney Docket No.: 2010581-1510 003, optionally wherein the subject is determined to have a genetic sequence that is or encodes an expanded CAG repeat. 455.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to have a genetic sequence that encodes a transcript that comprises an expanded CAG repeat in HTT and is fully complementary to the base sequence of WVE-003. 456.
  • a method comprising administering to a subject WVE-003 (or a salt form thereof), wherein the subject is determined to express a HTT transcript that comprises an expanded CAG repeat and is fully complementary to the base sequence of WVE-003. 457.
  • WVE-003 is formulated as a liquid formulation, optionally wherein the liquid formulation comprises WVE-003, sodium chloride and water and/or wherein the liquid formulation is reconstituted from a lyophilized preparation. 462.
  • a method for treating Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form; or a method for preventing Huntington’s disease, comprising administering or delivering to a subject suffering therefrom WVE-003 at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about
  • a dose of WVE-003 is administered in a pharmaceutical composition comprising or consisting of a WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier. 467. The method of any one of the preceding Embodiments, wherein each dose of WVE-003 is independently administered in one or more pharmaceutically acceptable salt forms, optionally wherein one form is WVE-003 pentadecasodium salt. 468. The method of any one of the preceding Embodiments, wherein each dose of WVE-003 is independently administered in a pharmaceutical composition comprising WVE-003 and a pharmaceutically acceptable carrier. 469.
  • each dose of WVE-003 is independently administered in a pharmaceutical composition comprising or consisting of a WVE-003 pentadecasodium salt and a pharmaceutically acceptable carrier. 470.
  • a method for treating Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 pentadecasodium salt: 183 of 265 12842751v1 Attorney Docket No.: 2010581-1510 10- 170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 471.
  • a method for preventing Huntington’s disease comprising administering or delivering to a subject suffering therefrom WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10- 200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, 184 of 265 12842751v1 Attorney Docket No.: 2010581-1510 about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form. 472.
  • WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10- 200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg
  • a method comprising administering or delivering to a subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, or about 168 mg) WVE-003 free acid form; or a method for decreasing the activity, expression, and/or level of a mutant HTT gene or its gene product in a subject, comprising administering or delivering to the subject WVE-003 pentadecasodium salt at a dose equivalent to about 10-200 mg (e.g., about 10-200 mg, about 10-190 mg, about 10-180 mg, about 10-170 mg, about 10 mg, about 20 mg, about 30 mg, 40 mg, about 50 mg, about 60 mg,
  • each dose of WVE-003 pentadecasodium salt is independently administered in a pharmaceutical composition comprising or consisting of WVE-003 and a pharmaceutically acceptable carrier. 477.
  • the pharmaceutical composition has a pH of about 6-8, optionally wherein the pharmaceutical composition has a pH of about 6.4-7.2 or about 7.3 or about 7.4. 479.
  • a dose is equivalent to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or 170 mg WVE-003 free acid form.
  • each dose is independently equivalent to about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or 170 mg WVE-003 free acid form.
  • level of mutant HTT polypeptide in cerebrospinal fluid is reduced by about 10%, 20%, 30%, 40%, 50% or more about or after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more weeks after a first dose. 490.
  • level of wtHTT transcript or polypeptide is reduced by no more than about 10%, 20%, 30%, 40% or 50%. 491.
  • the reduction is about 10%, 12%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more; and/or wherein the reduction is assessed for an individual subject; and/or wherein the reduction is assessed for a population of subjects, optionally wherein the population size is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000 or more subjects and/or wherein subjects in the population receive the same or different dosage regimen; and/or wherein one or more cerebrospinal fluid samples are utilized for reduction assessment. 493.
  • a dose is administered as WVE-003 pentadecasodium salt dissolved in aCSF, optionally wherein a dose is administered in a 20 mL aCSF solution, optionally wherein 20 mL CSF is taken out from a subject before administration of a dose. 499.
  • 500 The method of any of the previous Embodiments, wherein the subject receives or is exposed to an additional therapeutic agent. 501.
  • composition of any one of the preceding Embodiments wherein a form of WVE-003 in the composition is a pharmaceutically acceptable salt form and/or WVE-003 pentadecasodium salt, or each form of WVE-003 in the composition is independently a salt form, optionally a pharmaceutically acceptable salt form and/or WVE-003 pentadecasodium salt. 509. The composition of any one of the preceding Embodiments, wherein the composition is a drug substance and/or drug product. 510.
  • composition of any one of the preceding Embodiments, wherein the composition is lyophilized WVE-003 powder. 513.
  • the composition of any one of the preceding Embodiments, wherein WVE-003 in the composition is equivalent to about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or 170 mg WVE- 003 free acid form. 514.
  • the composition of any one of the preceding Embodiments, wherein the composition is packaged into a vial. 515.
  • the composition of any one of the preceding Embodiments, wherein the composition is reconstituted and diluted in artificial cerebrospinal fluid (aCSF). 516.
  • aCSF artificial cerebrospinal fluid
  • a vial comprising a composition of any one of the preceding Embodiments, optionally wherein the vial is filled with an inert gas, optionally wherein the inert gas is nitrogen.
  • a syringe comprising a composition of any one of the preceding Embodiments, optionally wherein the composition is a liquid composition wherein WVE-003 or WVE-003 pentadecasodium salt is dissolved in aCSF. 519.
  • the syringe of Embodiment 428 wherein the volume of the liquid composition is 20 mL. 520.
  • a method for releasing a WVE-003 preparation comprising utilizing IP-RP-UPLC to assess purity and/or impurities in the WVE-003 preparation and release the preparation if the purity and/or impurities meet certain criteria; or a method for assessing purity of WVE-003 utilizing IP-RP-UPLC. 525.
  • composition has a purity of about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% or more; wherein impurities in the composition are no more than about or about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, or 10%; and/or wherein stereochemical purity of WVE-003 is about 80%, 83%, or more. 531.
  • any one of the preceding Embodiments wherein the purity and/or impurities are measured by IP-RP-UPLC using area % at 260 nm, optionally using % at 260 nm and the Set A parameters; and/or wherein the amount of WVE-003 is measured by UV at 260 nm and 25.0 OD/mg. 532.
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-Ome modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2’-O-methoxyethyl C; 190 of 265 12842751v1 Attorney Docke
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ce
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphoroth
  • a method for slowing caudate atrophy comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxye
  • a method for reducing Total Motor Score (TMS) of a subject suffering from Huntington’s disease comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo
  • a method comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-Ome modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2’-O-methoxyethyl C; n001R represents a Rp
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5C
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphoroth
  • a method for slowing caudate atrophy comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxy
  • a method for reducing Total Motor Score (TMS) of a subject suffering from Huntington’s disease comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleo
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 8 weeks or less frequently, 196 of 265 12842751v1 Attorney Docket No.: 2010581-1510 wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents
  • a method comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 8 weeks or less frequently; the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; 197 of 265 12842751v1 Attorney Docket No.: 2010581-1510 WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5C
  • a method comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 8 weeks or less frequently; the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents a Rp n001
  • Embodiment 570 wherein the level of mHTT protein is assessed about 84 days after the last dose of the set. 574.
  • CSF cerebrospinal fluid
  • Embodiments 535-576 wherein level of mHTT protein in cerebrospinal fluid (CSF) of the subject is selectively reduced compared to level of wtHTT protein in CSF if assessed about 28, 56 and/or 84 days after the last dose of the set. 578.
  • the method of any one of Embodiments 576-581, wherein the last dose is the third dose. 583.
  • the method of any one of Embodiments 535-582, wherein ventricular volume after one or more WVE- 003 doses is comparable to a reference ventricular volume. 584.
  • the method of any one of Embodiments 583-584, wherein the reference ventricular volume is the baseline volume. 586.
  • the method of any one of Embodiments 583-585, wherein the last dose is the third dose. 587.
  • a method comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents a Rp
  • Embodiment 594 The method of Embodiment 593, wherein the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 0, 1, 2 or 3. 595.
  • CSF cerebrospinal fluid
  • Embodiments 593-602 wherein the regimen is demonstrated to achieve in a population of subjects about 30% or more mHTT protein reduction in cerebrospinal fluid (CSF) compared to a reference mHTT protein level in CSF if assessed about 28, 56, and/or 84 days after the last dose of the set, wherein the reference mHTT protein level is or comprises the mHTT protein level in CSF of a reference population, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003. 604.
  • CSF cerebrospinal fluid
  • the method of any one of Embodiments 593-611 wherein the regimen is demonstrated to achieve in a population of subjects ventricular volume change that is not larger than a reference ventricular volume change if assessed about 56 days after the last dose of the set, wherein the reference ventricular volume change is the ventricular volume change of a reference population, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003, and wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks. 613.
  • Embodiments 593-613 wherein the regimen is demonstrated to achieve in a population of subjects slowing of caudate atrophy compared to a placebo in a reference population of subjects, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003. 615.
  • each subject of the population independently has the T variant of rs362273 on the same allele as a non-expanded CAG repeat region in a HTT gene. 624.
  • a method comprising administering or delivering WVE-003 to a population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: 203 of 265 12842751v1 Attorney Docket No.: 2010581-1510 a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleo
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphoroth
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; 204 of 265 12842751v1 Attorney Docket No.: 2010581-1510 each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside;
  • a method for slowing caudate atrophy in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-me
  • a method for reducing Total Motor Score (TMS) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 8 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA 205 of 265 12842751v1 Attorney Docket No.: 2010581-1510 * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp
  • a method comprising administering or delivering WVE-003 to a population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5C
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorot
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo
  • a method for slowing caudate atrophy in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-
  • a method for reducing Total Motor Score (TMS) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 8 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-
  • the method of any one of Embodiments 624-644, wherein the expanded CAG repeat region comprises 36 or more (e.g., 36, 37, 38, 39, 40, 41, 42 or more) CAG repeats. 646.
  • the method of any one of Embodiments 624-647, wherein the number of doses in the set is two or more. 649.
  • the method of any one of Embodiments 624-652, wherein two or more doses in the set are administered about quarterly.
  • CSF cerebrospinal fluid
  • mHTT protein level is reduced by about 46% in cerebrospinal fluid (CSF) 56 days after the last dose of the set compared to a placebo, wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks.
  • CSF cerebrospinal fluid
  • mHTT protein level is reduced by about 44% in cerebrospinal fluid (CSF) 84 days after the last dose of the set compared to a placebo, wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks. 661.
  • Embodiments 624-662 wherein wtHTT protein is not reduced in cerebrospinal fluid (CSF) 56 days after the last dose of the set compared to a placebo, wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks 664.
  • ventricular volume change is comparable to a reference ventricular volume change if assessed about 56 days after the last dose of the set, wherein the reference ventricular volume change is the ventricular volume change of a reference population, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003, and wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks. 667.
  • ventricular volume change is not larger than a reference ventricular volume change if assessed about 56 days after the last dose of the set, wherein the reference ventricular volume change is the ventricular volume change of a reference population, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003, and wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks.
  • 668 The method of any one of Embodiments 665-667, wherein ventricular volume is assessed by MRI. 669.
  • Embodiment 671 wherein TMS is reduced compared to a placebo in a reference population of subjects if assessed about 56 days after the last dose of the set, wherein subjects of the reference population each independently receive a dose of placebo for each dose of WVE-003, and wherein the number of doses in the set is three, and the three doses are administered about every 8 weeks 673.
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, 211 of 265 12842751v1 Attorney Docket No.: 2010581-1510 wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-Ome modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2’-O-
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ce
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is 212 of 265 12842751v1 Attorney Docket No.: 2010581-1510 amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents
  • a method comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; the subject has a mutant HTT gene comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-Ome modification to a nucleoside; 213 of 265 12842751v1 Attorney Docket No.: 2010581-1510 *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5C
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) of a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorot
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a subject comprising administering or delivering to the subject WVE-003, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a subject comprising administering or delivering to the subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; the subject has a mutant HTT gene encoding mutant HTT protein and comprising a mutation that is amenable to an allele-specific knockdown of the mutant HTT gene; 215 of 265 12842751v1 Attorney Docket No.: 2010581-1510 WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: *S represents a Sp phosphorothioate linkage; m
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents a
  • a method comprising administering or delivering to a subject WVE-003, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 12 weeks or less frequently; the subject suffers from Huntington’s disease and has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001
  • Embodiments 696-697 wherein the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 3. 699.
  • a method comprising administering or delivering to a subject WVE-003, wherein: a set of three or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to
  • a method comprising administering or delivering to a subject WVE-003, wherein: 217 of 265 12842751v1 Attorney Docket No.: 2010581-1510 each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of three or more doses are administered or delivered about every 12 weeks or less frequently; the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O
  • a method comprising administering or delivering WVE-003 to a subject according to a regimen, wherein: the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA 218 of 265 12842751v1 Attorney Docket No.: 2010581-1510 * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate
  • Embodiment 709 wherein the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 0, 1, 2 or 3. 711.
  • the method of Embodiment 709, wherein the subject has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene and is HD-ISS Stage 1 or 2. 713.
  • the method of any one of Embodiments 709-715, wherein the expanded CAG repeat region comprises 36 or more (e.g., 36, 37, 38, 39, 40, 41, 42 or more) CAG repeats. 717.
  • Embodiments 709-716 wherein the subject has the T variant of rs362273 on the same allele as a non-expanded CAG repeat region in a HTT gene. 718.
  • a method comprising administering or delivering WVE-003 to a population of subjects, wherein: 219 of 265 12842751v1 Attorney Docket No.: 2010581-1510 a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; 220 of 265 12842751v1 Attorney Docket No.: 2010581-1510 each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’
  • a method for delaying onset of one or more symptoms of Huntington’s disease in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: a set of two or more doses are administered or delivered about every 12 weeks or less frequently, wherein each dose of the set is independently equivalent to about 30 mg WVE-003 free acid form; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5Ceo represents
  • a method comprising administering or delivering WVE-003 to a population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: 221 of 265 12842751v1 Attorney Docket No.: 2010581-1510 m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5C
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorothioate linkage; m5C
  • a method for selectively reducing level of mutant HTT protein over wild-type HTT protein in cerebrospinal fluid (CSF) in a population of subjects comprising administering or delivering WVE-003 to the population of subjects, wherein: each dose of WVE-003 is independently equivalent to about 30 mg WVE-003 free acid form; a set of two or more doses are administered or delivered about every 12 weeks or less frequently; each subject of the population independently has the A variant of rs362273 on the same allele as an expanded CAG repeat region in a HTT gene; and WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, wherein: m represents a 2’-OMe modification to a nucleoside; *S represents a Sp phosphorot

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Hospice & Palliative Care (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Entre autres, la présente divulgation concerne diverses technologies comprenant des compositions oligonucléotidiques chiralement régulées et des technologies de fabrication et d'utilisation de telles compositions oligonucléotidiques. Dans certains modes de réalisation, la présente divulgation concerne des technologies utiles pour l'inactivation spécifique d'un allèle de transcrits de huntingtine mutante. Dans certains modes de réalisation, la présente divulgation concerne des technologies utiles pour réduire l'expression, le niveau, la quantité et/ou l'activité de transcrits de huntingtine mutante ou de produits associés. Dans certains modes de réalisation, la présente divulgation concerne des méthodes de traitement de la maladie de Huntington.
PCT/US2025/035290 2024-06-25 2025-06-25 Compositions oligonucléotidiques et méthodes associées Pending WO2026006477A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202463664150P 2024-06-25 2024-06-25
US63/664,150 2024-06-25
USPCT/US2024/040849 2024-08-02
PCT/US2024/040849 WO2025030155A1 (fr) 2023-08-03 2024-08-02 Compositions d'oligonucléotides et procédés associés
US202463693161P 2024-09-10 2024-09-10
US63/693,161 2024-09-10

Publications (2)

Publication Number Publication Date
WO2026006477A1 true WO2026006477A1 (fr) 2026-01-02
WO2026006477A8 WO2026006477A8 (fr) 2026-04-23

Family

ID=98222997

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/035290 Pending WO2026006477A1 (fr) 2024-06-25 2025-06-25 Compositions oligonucléotidiques et méthodes associées

Country Status (1)

Country Link
WO (1) WO2026006477A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022219637A1 (fr) * 2021-04-14 2022-10-20 Prilenia Neurotherapeutics Ltd. Traitement de la maladie de huntington prodromique
WO2024035946A1 (fr) * 2022-08-11 2024-02-15 Wave Life Sciences Ltd. Compositions oligonucléotidiques et procédés associés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022219637A1 (fr) * 2021-04-14 2022-10-20 Prilenia Neurotherapeutics Ltd. Traitement de la maladie de huntington prodromique
WO2024035946A1 (fr) * 2022-08-11 2024-02-15 Wave Life Sciences Ltd. Compositions oligonucléotidiques et procédés associés

Also Published As

Publication number Publication date
WO2026006477A8 (fr) 2026-04-23

Similar Documents

Publication Publication Date Title
US20260055402A1 (en) Oligonucleotide compositions and methods thereof
AU2024315761A1 (en) Oligonucleotide compositions and methods thereof
KR102638276B1 (ko) 인트론 잔류의 감소
US20250197857A1 (en) Oligonucleotide compositions and methods thereof for exon skipping
HK1246648B (en) Compositions and methods for modulation of smn2 splicing in a subject
TWI769197B (zh) 用於治療多囊腎病之組成物
AU2025283628A1 (en) Composition comprising antisense oligonucleotide and use thereof for treatment of Duchenne muscular dystrophy
JP7612575B2 (ja) 筋萎縮性側索硬化症を治療及び予防するための組成物及び方法
KR20250155076A (ko) 안티센스 올리고머 제형
US20230364102A1 (en) Compositions and methods for the treatment of neurological disorders
US20230348905A1 (en) Methods for the reduction of z-aat protein levels
WO2026006477A1 (fr) Compositions oligonucléotidiques et méthodes associées
KR20260064686A (ko) 올리고뉴클레오타이드 조성물 및 이의 방법
CN116585344A (zh) 用于治疗奥尔波特综合征的方法
CA3224995A1 (fr) Procedes d'edition in vivo d'un gene hepatique
RU2793459C2 (ru) Композиции и способы модуляции smn2 сплайсинга у субъекта
WO2026072732A1 (fr) Compositions oligonucléotidiques et procédés associés permettant un saut d'exon

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25827492

Country of ref document: EP

Kind code of ref document: A1