WO2025202455A2 - Inhibiteurs d'expression et/ou de fonction - Google Patents

Inhibiteurs d'expression et/ou de fonction

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Publication number
WO2025202455A2
WO2025202455A2 PCT/EP2025/058565 EP2025058565W WO2025202455A2 WO 2025202455 A2 WO2025202455 A2 WO 2025202455A2 EP 2025058565 W EP2025058565 W EP 2025058565W WO 2025202455 A2 WO2025202455 A2 WO 2025202455A2
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WIPO (PCT)
Prior art keywords
strand
seq
nucleosides
nucleic acid
inhibitor
Prior art date
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Pending
Application number
PCT/EP2025/058565
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English (en)
Other versions
WO2025202455A3 (fr
Inventor
Natalie Wayne Pursell
Alexander Wolfgang Christian FISCHER
Alan Victor WHITMORE
Amy MCCARTHY
Ines DE SANTIAGO DOMINGOS DE JESUS
James LONGDEN
Alexandre DEBACKER
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.)
E Therapeutics PLC
Original Assignee
E Therapeutics PLC
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Publication date
Priority claimed from PCT/EP2024/064367 external-priority patent/WO2024245930A2/fr
Priority claimed from GBGB2417093.8A external-priority patent/GB202417093D0/en
Application filed by E Therapeutics PLC filed Critical E Therapeutics PLC
Publication of WO2025202455A2 publication Critical patent/WO2025202455A2/fr
Publication of WO2025202455A3 publication Critical patent/WO2025202455A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—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 against receptors or cell surface proteins
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/317—Chemical structure of the backbone with an inverted bond, e.g. a cap structure
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/344—Position-specific modifications, e.g. on every purine, at the 3'-end
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C—CHEMISTRY; METALLURGY
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    • C12N2320/00—Applications; Uses
    • C12N2320/10—Applications; Uses in screening processes
    • C—CHEMISTRY; METALLURGY
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    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications

Definitions

  • the present invention relates to nucleic acid compounds that inhibit the expression of the gene NR3C2, for use in the treatment and / or prevention of disease.
  • the NR3C2 gene is located on chromosome 4 at q31.23 and encodes the nuclear receptor subfamily 3 group C member 2 protein, also known as mineralocorticoid receptor.
  • the protein functions as a ligand-dependent transcription factor that mediates the effects of aldosterone in a variety of target tissues, including the distal parts of the nephron, the distal colon, the cardiovascular and central nervous systems, and brown adipose tissue.
  • the target tissues include the heart and liver.
  • a nucleic acid for inhibiting expression of NR3C2 comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2.
  • a nucleic acid for inhibiting expression of NR3C2 comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand modified sequences as listed in Table 3.
  • nucleic acid as described herein, wherein the first strand comprises nucleosides 2-18 of any one of the sequences according to the above Aspect A or Aspect B of the present invention, in particular wherein the first strand comprises nucleosides 2-18 of any one of the sequences defined in Tables 2 or 3.
  • nucleic acid according to the above Aspect A of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.
  • nucleic acid according to the above Aspect B of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.
  • nucleic acid according to the above Aspect A of the present invention, wherein the first strand comprises any one of the first strand sequences as listed in Table 2.
  • nucleic acid according to the above Aspect B of the present invention wherein the first strand comprises any one of the first strand modified sequences as listed in Table 3.
  • nucleic acid according to the above Aspect A of the present invention wherein the second strand comprises any one of the second strand sequences as listed in Table 2.
  • nucleic acid according to the above Aspect B of the present invention, wherein the second strand comprises any one of the second strand modified sequences as listed in Table 4.
  • nucleic acid according to the invention wherein the first strand has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 23 nucleosides.
  • nucleic acid according to the invention wherein the second strand has a length in the range of 17 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 19 or 21 or 23 nucleosides.
  • nucleic acid according to the invention wherein the duplex region of the nucleic acid is between 17 and 30 nucleosides in length, more preferably is 19 or 21 or 23 nucleosides in length.
  • nucleic acid according to the invention wherein the region of complementarity between the first strand and the portion of RNA transcribed from the NR3C2 gene is between 17 and 30 nucleosides in length.
  • nucleic acid in a further aspect, wherein the nucleic acid is an siRNA oligonucleoside.
  • a nucleic acid according to the invention wherein the second strand comprises 2 consecutive abasic nucleosides in the 5 ’ terminal region of the second strand, wherein one such abasic nucleoside is a terminal nucleoside at the 5 ’ terminal region of the second strand and the other abasic nucleoside is a penultimate nucleoside at the 5’ terminal region of the second strand, wherein:
  • said penultimate abasic nucleoside is connected to an adjacent first basic nucleoside in an adjacent 5’ near terminal region through a reversed intemucleoside linkage;
  • the reversed linkage is a 5-5’ reversed linkage; and (c) the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides.
  • nucleic acid according to the invention, wherein:
  • the first strand and the second strand each has a length of 23 nucleosides
  • two phosphorothioate intemucleoside linkages are respectively between three consecutive positions in said 5 ’ near terminal region of the second strand, wherein a first phosphorothioate intemucleoside linkage is present between said adjacent first basic nucleoside of (a) and an adjacent second basic nucleoside in said 5 ’ near terminal region of the second strand, and a second phosphorothioate intemucleoside linkage is present between said adjacent second basic nucleoside and an adjacent third basic nucleoside in said 5’ near terminal region of the second strand;
  • two phosphorothioate intemucleoside linkages are respectively between three consecutive positions in both 5 ’ and 3 ’ terminal regions of the first strand, whereby a terminal nucleoside respectively at each of the 5’ and 3’ terminal regions of said first strand is each attached to a respective 5’ and 3’ adjacent penultimate nucleoside by a phosphorothioate intemucleoside linkage, and each first 5 ’ and 3 ’ penultimate nucleoside is attached to a respective 5’ and 3’ adjacent antepenultimate nucleoside by a phosphorothioate intemucleoside linkage; and
  • the second strand of the nucleic acid is conjugated directly or indirectly to one or more ligand moieties at the 3’ terminal region of the second strand.
  • nucleic acid according to the invention wherein the 2 consecutive inverted abasic nucleosides in the 5’ terminal region of the second strand present as the following 5 ’ terminal motif:
  • T represents a 2’Me ribose modification
  • B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of the second strand
  • Z represents the remaining 19 contiguous basic nucleosides of said second strand.
  • nucleic acid in a further aspect, wherein the nucleic acid is conjugated directly or indirectly to one or more ligand moieties, optionally wherein said ligand moiety is present at a terminal region of the second strand, preferably at the 3 ’ terminal region thereof.
  • nucleic acid according to the invention wherein the ligand moiety comprises:
  • nucleic acid according to the invention wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the nucleic acid, preferably at the 3’ terminal region thereof.
  • nucleic acid according to the invention comprising the structure: wherein:
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 290, SEQ ID NO: 270, SEQ ID NO: 238, SEQ ID NO: 245, SEQ ID NO: 283, SEQ ID NO: 235, SEQ ID NO: 226, SEQ ID NO: 335, SEQ ID NO: 228 or SEQ ID NO: 410.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 290.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 736, SEQ ID NO: 716, SEQ ID NO: 684, SEQ ID NO: 691 or SEQ ID NO: 729.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 716.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 513, SEQ ID NO: 493, SEQ ID NO: 461, SEQ ID NO: 468 or SEQ ID NO: 506.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 959, SEQ ID NO: 939, SEQ ID NO: 907, SEQ ID NO: 914, SEQ ID NO: 952, SEQ ID NO: 904, SEQ ID NO: 895, SEQ ID NO: 1004, SEQ ID NO: 897, SEQ ID NO: 897 or SEQ ID NO: 1079.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 959, SEQ ID NO: 939, SEQ ID NO: 907, SEQ ID NO: 914 or SEQ ID NO: 952.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 959. [0049] In a further aspect, the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 939.
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • conjugate for inhibiting expression of NR3C2 target gene in a cell comprising a nucleic acid as disclosed herein and one or more ligand moieties.
  • composition comprising a nucleic acid as disclosed herein, in combination with a pharmaceutically acceptable excipient or carrier.
  • nucleic acid or pharmaceutical composition for use in therapy.
  • nucleic acid or pharmaceutical composition for use in the treatment of heart failure with reduced ejection fraction (HFrEF), such as an ischaemic heart disease, in particular myocardial infarction and/or symptoms thereof, and/or for use in the treatment of heart failure with preserved ejection fraction (HFpEF) and/or symptoms thereof.
  • HFrEF reduced ejection fraction
  • ischaemic heart disease in particular myocardial infarction and/or symptoms thereof
  • HFpEF preserved ejection fraction
  • nucleic acid or pharmaceutical composition as disclosed herein, wherein the nucleic acid or the pharmaceutical composition is administered after myocardial infarction.
  • the invention relates to an inhibitor of expression and / or function of NR3C2, wherein said inhibitor is conjugated to one or more ligand moieties.
  • the invention relates to an inhibitor according to the invention, wherein said inhibitor is an siRNA oligomer.
  • the invention relates to an inhibitor of expression and / or function of NR3C2, wherein said inhibitor is an siRNA oligomer.
  • the invention relates to an inhibitor according to the invention, for use in prevention or treatment of an ischaemic heart disease, such as myocardial infarction.
  • the invention relates to an inhibitor according to the invention, wherein said one or more ligand moieties comprise one or more GalNAc ligands or comprise one or more GalNAc ligand derivatives.
  • the invention relates to an inhibitor for use according to the invention, wherein said one or more ligand moieties comprise one or more GalNAc ligand derivatives.
  • the invention relates to an inhibitor for use according to the invention, wherein the target of the inhibitor is NR3C2.
  • a nucleic acid for inhibiting expression of NR3C2 comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2.
  • a nucleic acid for inhibiting expression of NR3C2 comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand modified sequences as listed in Table 3.
  • nucleic acid as described herein, wherein the first strand comprises nucleosides 2-18 of any one of the sequences according to the above Aspect C or Aspect D of the present invention.
  • nucleic acid according to the above Aspect C of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.
  • nucleic acid according to the above Aspect C of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand sequences as listed in Table 2, and wherein the duplex region comprises at least 14, 15, 16 or 17 complementary base pairs.
  • nucleic acid according to the above Aspect D of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the second strand has a region of at least 85% complementarity over the 17 contiguous nucleosides to the first strand.
  • nucleic acid according to the above further Aspect D of the present invention, wherein the second strand comprises a nucleoside sequence of at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the second strand modified sequences as listed in Table 4, and wherein the duplex region comprises at least 14, 15, 16 or 17 complementary base pairs.
  • nucleic acid according to the above Aspect C of the present invention, wherein the first strand comprises any one of the first strand sequences as listed in Table 2.
  • nucleic acid according to the above Aspect D of the present invention, wherein the first strand comprises any one of the first strand modified sequences as listed in Table 3.
  • the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or
  • the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein one or more nucleosides on the first strand and / or the second strand is / are modified, to form modified nucleosides.
  • the invention relates to an inhibitor or an inhibitor for use according to the invention, wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5’ or 3’ terminal region of the second strand of the siRNA oligomer, preferably at the 3’ terminal region thereof.
  • the invention relates to an inhibitor or an inhibitor for use according to the invention, having the structure: wherein:
  • Ri at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl;
  • Xi and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that:
  • Z is an oligomer
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor according to one or more preceding claims, in combination with a pharmaceutically acceptable excipient or carrier.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor according to the invention, in combination with a pharmaceutically acceptable excipient or carrier, for use in the treatment of an ischaemic heart disease, such as myocardial infarction.
  • the pharmaceutical composition according to the invention is for use in the treatment of an ischaemic heart disease, such as myocardial infarction, whereby the pharmaceutical composition alleviates symptoms of an ischaemic heart disease, in particular myocardial infarction, more particularly an acute myocardial infarction.
  • the pharmaceutical composition of the invention may be administered after myocardial infarction, in particular for cardioprotection, for reducing infarct size and/or reducing reperfusion arrhythmias.
  • the invention relates to a method of treating or preventing a disease or disorder related to an ischaemic heart disease, such as myocardial infarction, which comprises administering to a patient an inhibitor of NR3C2, such as an inhibitor as defined according to one or more preceding aspects.
  • a disease or disorder related to an ischaemic heart disease such as myocardial infarction
  • the invention relates to NR3C2 for use as a biomarker of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the invention relates to NR3C2 for use in an in vivo method of predicting susceptibility to an ischaemic heart disease, such as myocardial infarction, typically by monitoring the sequence and/ or level of expression and / or function of NR3C2 in a sample obtained from a patient.
  • the invention relates to an inhibitor or composition according to the invention, in the preparation of a medicament for use in the treatment of an ischaemic heart disease, such as myocardial infarction.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 228, SEQ ID NO: 238, SEQ ID NO: 243, SEQ ID NO: 235, SEQ ID NO: 245 and SEQ ID NO: 250.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 238.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 245.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 674, SEQ ID NO: 684, SEQ ID NO: 689, SEQ ID NO: 681, SEQ ID NO: 691 and SEQ ID NO: 696.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 684.
  • the invention relates to an inhibitor according to the invention, wherein the first strand comprises SEQ ID NO: 691.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 451, SEQ ID NO: 461, SEQ ID NO: 466, SEQ ID NO: 458, SEQ ID NO: 468 and SEQ ID NO: 473.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 461.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 468.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 907.
  • the invention relates to an inhibitor according to the invention, wherein the second strand comprises SEQ ID NO: 914.
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor according to the invention, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor for use according to the invention, wherein said inhibitor is an siRNA oligomer.
  • the invention relates to an inhibitor for use according to the invention, wherein said one or more ligand moieties comprise one or more GalNAc ligands or comprise one or more GalNAc ligand derivatives. [0146] In a further aspect, the invention relates to an inhibitor for use according to the invention, wherein the target of the inhibitor is NR3C2.
  • nucleic acid for inhibiting expression of NR3C2, for use in the treatment of heart failure with preserved ejection fraction (HFpEF), comprising a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is: (i) at least partially complementary to a portion of RNA transcribed from the NR3C2 gene, and (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2.
  • composition comprising a nucleic acid for use as disclosed herein, in combination with a pharmaceutically acceptable excipient or carrier.
  • the invention relates to an inhibitor for use according to the invention, wherein the second strand comprises: i) 2, or more than 2, abasic nucleosides in a terminal region of the second strand; and / or ii) 2, or more than 2, abasic nucleosides in either the 5 ’ or 3 ’ terminal region of the second strand; and / or iii) 2, or more than 2, abasic nucleosides in either the 5 ’ or 3 ’ terminal region of the second strand, wherein the abasic nucleosides are present in an overhang as herein described; and / or iv) 2, or more than 2, consecutive abasic nucleosides in a terminal region of the second strand, wherein preferably one such abasic nucleoside is a terminal nucleoside; and / or v) 2, or more than 2, consecutive abasic nucleosides in either the 5 ’ or 3 ’ terminal region
  • the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or (2) the reversed linkage is a 3-3’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 5’3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides.
  • the invention relates to an inhibitor for use according to the invention, wherein the reversed intemucleoside linkage is at a terminal region which is distal to the 5 ’ terminal region of the second strand, or at a terminal region which is distal to the 3’ terminal region of the second strand.
  • the invention relates to an inhibitor for use according to the invention, wherein the reversed intemucleoside linkage is a 3’3 reversed linkage.
  • the invention relates to an inhibitor for use according to the invention, wherein the reversed intemucleoside linkage is a 5’5 reversed linkage.
  • the invention relates to an inhibitor for use according to the invention, wherein one or more nucleosides on the first strand and / or the second strand is / are modified, to form modified nucleosides.
  • the invention relates to an inhibitor for use according to the invention, wherein the modification is a modification at the 2 ’-OH group of the ribose sugar, optionally selected from 2'-Me or 2’-F modifications.
  • the invention relates to an inhibitor for use according to the invention, wherein the second strand comprises a 2’-F modification at position 7 and / or 9, and / or 11 and / or 13, counting from position 1 of said second strand.
  • the invention relates to an inhibitor for use according to the invention, wherein the first and second strand each comprise 2'-Me and 2’-F modifications.
  • the invention relates to an inhibitor for use according to the invention, which is an siRNA, wherein the siRNA comprises at least one thermally destabilizing modification, suitably at one or more of positions 1 to 9 of the first strand counting from position 1 of the first strand, and / or at one or more of positions on the second strand aligned with positions 1 to 9 of the first strand, wherein the destabilizing modification is selected from a modified unlocked nucleic acid (IMUNA) and a glycol nucleic acid (GNA), preferably a glycol nucleic acid.
  • IMUNA modified unlocked nucleic acid
  • GNA glycol nucleic acid
  • the invention relates to an inhibitor for use according to the invention, wherein the siRNA comprises at least one thermally destabilizing modification at position 7 of the first strand, counting from position 1 of the first strand.
  • the invention relates to an inhibitor for use according to the invention, which is an siRNA, wherein the siRNA comprises 3 or more 2’-F modifications at positions 7 to 13 of the second strand, such as 4, 5, 6 or 7 2’-F modifications at positions 7 to 13 of the second strand, counting from position 1 of said second strand
  • the invention relates to an inhibitor for use according to the invention, which is an siRNA, wherein said second strand comprises at least 3, such as 4, 5 or 6, 2’-Me modifications at positions 1 to 6 of the second strand, counting from position 1 of said second strand.
  • the invention relates to an inhibitor for use according to the invention, which is an siRNA, wherein said first strand comprises at least 5 2’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region, or at least within 1 or 2 nucleosides from the terminal nucleoside at the 3’ terminal region.
  • the invention relates to an inhibitor for use according to the invention, which is an siRNA wherein said first strand comprises 7 2’-Me consecutive modifications at the 3’ terminal region, preferably including the terminal nucleoside at the 3’ terminal region.
  • the invention relates to an inhibitor for use according to the invention, wherein the siRNA oligomer further comprises one or more phosphorothioate intemucleoside linkages.
  • the invention relates to an inhibitor for use according to the invention, wherein the oligomer is an siRNA and the second strand of the siRNA is conjugated directly or indirectly to one or more ligand moiety(s), wherein said ligand moiety is typically present at a terminal region of the second strand, preferably at the 3 ’ terminal region thereof.
  • the invention relates to an inhibitor for use according to the invention, wherein the ligand moiety comprises: i) one or more GalNAc ligands; and / or ii) one or more GalNAc ligand derivatives; and / or iii) one or more GalNAc ligands and / or GalNAc ligand derivatives conjugated to said siRNA through a linker.
  • the invention relates to an inhibitor for use according to the invention, wherein said one or more GalNAc ligands and / or GalNAc ligand derivatives are conjugated directly or indirectly to the 5 ’ or 3 ’ terminal region of the second strand of the siRNA oligomer, preferably at the 3 ’ terminal region thereof.
  • the invention relates to an inhibitor for use according to the invention, wherein the ligand moiety comprises:
  • the invention relates to an inhibitor for use according to the invention, having the structure: wherein:
  • Ri at each occurrence is independently selected from the group consisting of hydrogen, methyl and ethyl;
  • Xi and X2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur;
  • m is an integer of from 1 to 6;
  • n is an integer of from 1 to 10;
  • q, r, s, t, v are independently integers from 0 to 4, with the proviso that:
  • Z is an oligomer
  • the invention relates to an inhibitor for use according to the invention, having the structure: wherein: r and s are independently an integer selected from 1 to 16; and
  • Z is an oligomer
  • the invention relates to an inhibitor for use according to the invention, formulated as a pharmaceutical composition with an excipient and / or carrier.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an inhibitor according to the invention, in combination with a pharmaceutically acceptable excipient or carrier, for use in the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the invention relates to the use of NR3C2 as a target for identifying one or more therapeutic agents for the treatment of heart failure with preserved ejection fraction (HFpEF).
  • HFpEF preserved ejection fraction
  • the invention relates to a method of treating or preventing a disease or disorder related to heart failure with preserved ejection fraction (HFpEF), which comprises administering to a patient an inhibitor of NR3C2, such as an inhibitor as defined according to the invention.
  • HFpEF preserved ejection fraction
  • the invention relates to NR3C2 for use as a biomarker of heart failure with preserved ejection fraction (HFpEF) and associated conditions such as restrictive and hypertrophic cardiomyopathies of any etiology, constrictive pericarditis, and valvular heart disease.
  • the invention relates to NR3C2 for use in an in vivo method of predicting susceptibility to HFpEF, typically by monitoring the sequence and/ or level of expression and / or function of NR3C2 in a sample obtained from a patient.
  • the invention relates to a method of predicting susceptibility to HFpEF, and optionally treating HFpEF, in a patient, said method comprising:
  • the invention relates to an inhibitor for use according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 228, SEQ ID NO: 238, SEQ ID NO: 243, SEQ ID NO: 235, SEQ ID NO: 245 and SEQ ID NO: 250.
  • the invention relates to an inhibitor for use according to the invention, wherein the first strand comprises SEQ ID NO: 245.
  • the invention relates to an inhibitor for use according to the invention, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 674, SEQ ID NO: 684, SEQ ID NO: 689, SEQ ID NO: 681, SEQ ID NO: 691 and SEQ ID NO: 696.
  • the invention relates to an inhibitor for use according to the invention, wherein the first strand comprises SEQ ID NO: 684.
  • the invention relates to an inhibitor for use according to the invention, wherein the first strand comprises SEQ ID NO: 691.
  • the invention relates to an inhibitor for use according to the invention, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 451, SEQ ID NO: 461, SEQ ID NO: 466, SEQ ID NO: 458, SEQ ID NO: 468 and SEQ ID NO: 473.
  • the invention relates to an inhibitor for use according to the invention, wherein the second strand comprises SEQ ID NO: 461.
  • the invention relates to an inhibitor for use in the treatment of HFpEF, wherein the second strand comprises SEQ ID NO: 513.
  • the invention relates to an inhibitor for use in the treatment of HFpEF, wherein the second strand comprises any one of the following sequences: SEQ ID NO: 959, SEQ ID NO: 939, SEQ ID NO: 907, SEQ ID NO: 914 or SEQ ID NO: 952.
  • the invention relates to an inhibitor for use in the treatment of HFpEF, wherein the second strand comprises SEQ ID NO: 959.
  • the invention relates to an inhibitor for use in the treatment of HFpEF, wherein the second strand comprises SEQ ID NO: 939.
  • the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:
  • the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence: [0232] In a further aspect, the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence: [0236] In a further aspect, the invention relates to an inhibitor for use in the treatment of HFpEF, comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from the following first and second sequence:
  • Figure 1 Linker and ligand portions of constructs suitable for use according to the present invention including tether la. While Figure 1 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein.
  • Figure 1 depicts as a product molecules based on the linker and ligand portions as specifically depicted in Figure 1 attached to an oligonucleoside moiety as also depicted herein
  • this product may alternatively further comprise, or consist essentially of, molecules wherein the linker and ligand portions are essentially as depicted in Figure 1 attached to an oligonucleoside moiety but having the F substituent as shown in Figure 1 on the cyclo-octyl ring replaced by a substituent, which could occur as a result of hydrolytic displacement, such as an OH substituent, or the OH substituent could be synthesized as a linker in its own right.
  • tether la constructs can consist essentially of molecules having linker and ligand portions specifically as depicted in Figure 1, with a F substituent on the cyclo-octyl ring; or (b) tether la constructs can consist essentially of molecules having linker and ligand portions essentially as depicted in Figure 1 but having the F substituent as shown in Figure 1 on the cyclooctyl ring replaced by an OH substituent, or (c) tether la constructs can comprise a mixture of molecules as defined in (a) and/or (b).
  • Figure 2 Linker and ligand portions of constructs suitable for use according to the present invention including tether lb. While Figure 2 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein.
  • Figure 3 Linker and ligand portions of constructs suitable for use according to the present invention including tether 2a. While Figure 3 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein.
  • Figure 4 Linker and ligand portions of constructs suitable for use according to the present invention including tether 2b. While Figure 4 depicts the linker to be conjugated to an oligonucleotide, it is to be understood that the present invention also encompasses conjugates of the same linker with an oligonucleoside as disclosed herein.
  • Figures 7a and 7b Inverted abasic constructs that can be used with nucleic acid sequences according to the present invention as described herein.
  • a GalNAc linker is attached to the 5’ end region of the sense strand in use (not depicted in Figure 7a).
  • a GalNAc linker is attached to the 3’ end region of the sense strand in use (not depicted in Figure 7b).
  • iaia as shown at the 3’ end region of the sense strand in Figure 7a represents (i) two abasic nucleosides provided as the penultimate and terminal nucleosides at the 3’ end region of the sense strand, (ii) wherein a 3 ’-3 ’ reversed linkage is provided between the antepenultimate nucleoside (namely at position 21 of the sense strand, wherein position 1 is the terminal 5’ nucleoside of the sense strand) and the adjacent penultimate abasic residue of the sense strand, and (iii) the linkage between the terminal and penultimate abasic nucleosides is 5 ’-3’ when reading towards the 3’ end region comprising the terminal and penultimate abasic nucleosides.
  • iaia as shown at the 5’ end region of the sense strand in Figure 7b represents (i) two abasic nucleosides provided as the penultimate and terminal nucleosides at the 5’ end region of the sense strand, (ii) wherein a 5 ’-5 ’ reversed linkage is provided between the antepenultimate nucleoside (namely at position 1 of the sense strand, not including the iaia motif at the 5’ end region of the sense strand in the nucleoside position numbering on the sense strand) and the adjacent penultimate abasic residue of the sense strand, and (iii) the linkage between the terminal and penultimate abasic nucleosides is 3 ’-5’ when reading towards the 5’ end region comprising the terminal and penultimate abasic nucleosides.
  • Figures 8a and 8b Duplex constructs according to Table 5.
  • Figure 9 The correlation between predicted and experimentally determined siRNA efficacy values i.e. maximum RNA knockdown where 1 represents maximum knockdown and 0 is no reduction in mRNA levels. Data displayed are for the test dataset in the best performing siRNAdesignR model.
  • Figure 10 Performance metrics for the best performing siRNAdesignR model in the test data set and also the validation dataset. In both cases the model scored above 0.5 in the Precision@20 metric, and the best performing siRNA (experimentally determined) was in the top 20 predictions of the model (nSiRNAsForBest).
  • Figure 13 Change in SLC25A5 mRNA knockdown over 28 days following one subcutaneous dose of siRNA at day 0. As mRNA measurements are taken from liver tissue measurements are taken from different mice at each time point. Data are mean +/- standard deviation from 16 mice per timepoint per dose, normalised to saline control.
  • Figure 15b shows an exemplary branched configuration for a conjugate.
  • Figure 30 Left ventricle (LV) geometry assessed by echocardiography after 6 weeks of treatments with vehicle or ETX-M00002590 at 10 mg/kg or eplerenone at 1 g/kg diet or empagliflozin at lOmg/kg in mice.
  • LVAWd and LVAWs anterior wall thickness in diastole and systole
  • the term "region of complementarity" refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule.
  • a double stranded nucleic acid e.g., an siRNA agent of the invention includes a nucleotide mismatch in the antisense strand.
  • the “second strand” (also called the sense strand or passenger strand herein, and which can be used interchangeably herein), refers to the strand of a nucleic acid e.g., siRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein.
  • Oligonucleotides are short nucleic acid polymers. Whilst oligonucleotides contain phosphodiester bonds between the nucleoside component thereof (base plus sugar), the present invention is not limited to oligonucleotides always joined by such a phosphodiester bond between adjacent nucleosides, and other oligomers of nucleosides joined by bonds which are bonds other than a phosphate bond are contemplated. For example, a bond between nucleotides may be a phosphorothioate bond. Therefore, the term “oligonucleoside” herein covers both oligonucleotides and other oligomers of nucleosides.
  • An oligonucleoside which is a nucleic acid having at least a portion which is an oligonucleotide is preferred according to the present invention.
  • An oligonucleoside having one or more, or a majority of, phosphodiester backbone bonds between nucleosides is also preferred according to the present invention.
  • An oligonucleoside having one or more, or a majority of, phosphodiester backbone bonds between nucleosides, and having one or more phosphorothioate backbone bonds between nucleosides (typically in a terminal region of the first and / or second strands) is also preferred according to the present invention.
  • the nucleic acid according to the invention is a double stranded oligonucleoside comprising one or more phosphorothioate backbone bonds between nucleosides. Accordingly, in all instances in which the present application refers to an oligonucleotide, particularly in the chemical structures disclosed herein, the oligonucleotide may equally be an oligonucleoside as defined herein.
  • a double stranded nucleic acid e.g., siRNA agent of the invention includes a nucleoside mismatch in the sense strand. In some embodiments, the nucleoside mismatch is, for example, within 5, 4, 3, 2, or 1 nucleosides from the 3 '-end of the nucleic acid e.g., siRNA.
  • RNAi agent refers to an agent that contains RNA, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway.
  • siRNA directs the sequencespecific degradation of mRNA through RNA interference (RNAi).
  • a double stranded RNA is referred to herein as a “double stranded siRNA (dsiRNA) agent", “double stranded siRNA (dsiRNA) molecule”, “double stranded RNA (dsRNA) agent”, “double stranded RNA (dsRNA) molecule”, “dsiRNA agent”, “dsiRNA molecule”, or “dsiRNA”, which refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having "sense” and “antisense” orientations with respect to a target RNA.
  • each strand of the nucleic acid e.g., a dsRNA molecule
  • each or both strands can also include one or more non- ribonucleosides, e.g., a deoxyribonucleoside or a modified ribonucleoside.
  • an "siRNA” may include ribonucleosides with chemical modifications.
  • modified nucleoside refers to a nucleoside having, independently, a modified sugar moiety, a modified intemucleoside linkage, or modified nucleobase, or any combination thereof.
  • modified nucleoside encompasses substitutions, additions, or removal of, e.g., a functional group or atom, to intemucleoside linkages, sugar moieties, or nucleobases. Any such modifications, as used in a siRNA type molecule, are encompassed by "iRNA” or “RNAi agent” or “siRNA” or “siRNA agent” for the purposes of this specification and claims.
  • the duplex region of a nucleic acid of the invention e.g., a dsRNA may range from about 9 to 40 base pairs in length such as 9 to 36 base pairs in length, e.g., about 15- 30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15- 21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18- 27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18- 20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20- 27, 20-26, 20-25, 20-24, 20-24
  • the two strands forming the duplex structure may be different portions of one larger molecule, or they may be separate molecules e.g., RNA molecules.
  • nucleoside overhang refers to at least one unpaired nucleoside that extends from the duplex structure of a double stranded nucleic acid.
  • a ds nucleic acid can comprise an overhang of at least one nucleoside; alternatively, the overhang can comprise at least two nucleosides, at least three nucleosides, at least four nucleosides, at least five nucleosides, or more.
  • a nucleoside overhang can comprise or consist of a nucleoside analog, including a deoxynucleoside.
  • the overhang(s) can be on the sense strand, the antisense strand, or any combination thereof.
  • the /nucleoside(s) of an overhang can be present on the 5'-end, 3'-end, or both ends of either an antisense or sense strand.
  • the antisense strand has a 1-10 nucleoside, e.g., 0-3, 1-3, 2-4, 2-5, 4-10, 5- 10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleoside overhangs at the 3'-end or the 5'-end.
  • nucleic acids of the invention include those with no nucleoside overhang at one end or with no nucleoside overhangs at either end.
  • Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12-16 hours followed by washing (see, e.g., "Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press).
  • Complementary sequences within nucleic acid include basepairing of the oligonucleoside or polynucleoside comprising a first nucleoside sequence to an oligonucleoside or polynucleoside comprising a second nucleoside sequence over the entire length of one or both nucleoside sequences.
  • Such sequences can be referred to as "fully complementary” with respect to each other herein.
  • first sequence is referred to as “substantially complementary” with respect to a second sequence herein
  • the two sequences can be fully complementary, or they can form one or more mismatched base pairs, such as 2, 4, or 5 mismatched base pairs, but preferably not more than 5, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g. , inhibition of gene expression via a RISC pathway.
  • Overhangs shall not be regarded as mismatches with regard to the determination of complementarity.
  • a nucleic acid e.g., dsRNA comprising one oligonucleoside 17 nucleosides in length and another oligonucleoside 19 nucleosides in length, wherein the longer oligonucleoside comprises a sequence of 17 nucleosides that is fully complementary to the shorter oligonucleoside, can yet be referred to as "fully complementary”.
  • a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 19 base pairs and comprising not more than 1, 2, 3, 4, or 5 mismatched base pairs. In certain embodiments, a first and second strand of the nucleic acid according to the invention are partially complementary if they form a duplex region having a length of 21 base pairs comprising not more than 1, 2, 3, 4, or 5 mismatched base pairs.
  • a target for inhibition disclosed herein may be, without limitation, an mRNA, polypeptide, protein, or gene.
  • the invention relates to an inhibitor suitable for use, or for use, in treatment of an ischaemic heart disease, in particular myocardial infarction.
  • the invention relates to an inhibitor suitable for use, or for use, in treatment of heart failure with reduced ejection fraction (HFrEF).
  • Inhibitors disclosed herein, including the specific oligonucleotide sequences disclosed herein, may be used in the treatment of any of the diseases disclosed herein, included HFrEF and HFpEF.
  • Inhibitors of the invention include nucleic acids such as siRNAs, antibodies, and antigen binding fragments thereof, e.g., monoclonal antibodies, polypeptides, antibody-drug conjugates, and small molecules. Preferred are nucleic acids such as siRNA.
  • the nucleic acid comprises a first strand comprising a sequence that is at least partially complementary to a portion of RNA transcribed from the NR3C2 gene (SEQ ID NO: 1116). In a preferred embodiment, the nucleic acid comprises a first strand comprising a sequence that is at least partially complementary to a NR3C2 mRNA.
  • the nucleic acid for inhibiting expression of NR3C2 comprises a duplex region that comprises a first strand and a second strand that is at least partially complementary to the first strand, wherein said first strand is at least partially complementary to a portion of RNA transcribed from the NR3C2 gene.
  • the invention specifically contemplates the use of abasic nucleosides as disclosed in PCT/US22/74223 (WO 2023/059948). In particular, it specifically contemplates the use of abasic nucleosides as described in paragraphs [0141] - [0165] (pages 34 - 40) of the published PCT specification, the disclosure of which is hereby incorporated by reference.
  • Nm represents a 2’Me ribose modified nucleoside
  • Said GalNAc ligand may be conjugated directly or indirectly to the 5 ’ or 3 ’ terminal region of the second strand of the nucleic acid, preferably at the 3 ’ terminal region thereof.
  • GalNAc ligands are well known in the art and described in, inter alia, EP3775207A1.
  • the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide” may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide” may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds.
  • the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide” may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide” may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds.
  • the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide” may be any nucleic acid disclosed herein. Accordingly, the "oligonucleotide” may comprise other bonds than a phosphodiester bond, such as one or more phosphorothioate bonds.
  • the nucleic acid according to the invention is a double stranded oligonucleoside as defined herein and the linker is conjugated to the second strand, more preferably to the 3' terminal region of the second strand, via a phosphodiester bond.
  • the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond.
  • the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified or unmodified second strand comprising or consisting of any one of SEQ ID NO:447 to SEQ ID NO:669, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one SEQ ID NO:447 to SEQ ID NO:669, via a phosphodiester bond.
  • the GalNAc ligand is comprised in any one of the linkers shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide" represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably wherein the linker is conjugated to the 3' terminal region of the second strand, i.e., to the 3' terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, via a phosphodiester bond.
  • the GalNAc ligand is comprised in the linker shown in Figures 1 to 4 or Figure 5 (Formula XI), wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, wherein the second strand has the following structure: wherein:
  • T represents a 2’Me ribose modification
  • B represents the nucleoside bases of the first two basic nucleosides in the 5 ’ terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, and
  • Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914.
  • the GalNAc ligand is comprised in the linker shown in Figure 5 (Formula XI), wherein the "oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, wherein the second strand has the following structure: wherein:
  • T represents a 2’Me ribose modification
  • B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914, and
  • Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO: 1115, preferably of any one of SEQ ID NO: 897, SEQ ID NO: 907, SEQ ID NO: 912, SEQ ID NO: 904, SEQ ID NO: 914, and SEQ ID NO: 919, more preferably SEQ ID NO: 907 or SEQ ID NO: 914.
  • the GalNAc ligand is comprised in the linker shown in Figure 3, wherein the “oligonucleotide” represents a nucleic acid according to the invention, wherein the nucleic acid according to the invention comprises a modified second strand comprising or consisting of any one of SEQ ID NO:893 to SEQ ID NO: 1115, wherein the second strand has the following structure: wherein:
  • T represents a 2’Me ribose modification
  • B represents the nucleoside bases of the first two basic nucleosides in the 5' terminal region of any one of SEQ ID NO:893 to SEQ ID NO: 1115, and
  • Z represents the remaining 19 contiguous basic nucleosides of any one of SEQ ID NO:893 to SEQ ID NO: 1115, respectively.
  • compounds of the invention comprise the following structure:
  • Ai is hydrogen, or a suitable hydroxy protecting group; a is 3; and b is an integer of 3.
  • exemplary compounds of the invention comprise a ‘linker moiety’, as depicted in Formula (I*), that is part of an overall ‘linker’.
  • r and s are independently an integer selected from 1 to 16;
  • Z is an oligonucleoside moiety.
  • exemplary compounds of the invention comprise an overall linker that is located between the oligonucleoside moiety and the ligand moiety of these compounds.
  • the overall linker thereby ‘links’ the oligonucleoside moiety and the ligand moiety to each other.
  • the overall linker is often notionally envisaged as comprising one or more linker building blocks.
  • linker portion that is depicted as the ‘linker moiety’ as represented in Formula (I*) positioned adjacent the ligand moiety and attaching the ligand moiety, typically via a branch point, directly or indirectly to the oligonucleoside moiety.
  • the linker moiety as depicted in Formula (I*) can also often be referred to as the ‘ligand arm or arms’ of the overall linker.
  • linker portion between the oligonucleoside moiety and the branch point, which is often referred to as the ‘tether moiety’ of the overall linker, ‘tethering’ the oligonucleoside moiety to the remainder of the conjugated compound.
  • linker moieties and / or ‘tether moieties’ can be envisaged by reference to the linear and / or branched configurations as set out above.
  • the ‘tether moiety’ comprises the group of atoms between Z, namely the oligonucleoside moiety, and the linker moiety.
  • r is an integer selected from 4 to 14. In some embodiments, r is 6. In some embodiments, r is 12.
  • exemplary compounds of the invention comprise the following structure:
  • r is 6 and s is 6.
  • Ai is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and b is an integer of 2 to 5; or
  • Ai is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and c and d are independently integers of 1 to 6; or
  • Ai is hydrogen, or a suitable hydroxy protecting group; a is an integer of 2 or 3; and e is an integer of 2 to 10.
  • the invention provides a cell containing a nucleic acid, such as inhibitory RNA [RNAi] as described herein.
  • a nucleic acid such as inhibitory RNA [RNAi] as described herein.
  • the invention provides a vector comprising an oligonucleotide inhibitor, e.g., an iRNA e.g., siRNA.
  • an oligonucleotide inhibitor e.g., an iRNA e.g., siRNA.
  • the pharmaceutically acceptable composition may comprise an excipient and or carrier.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol
  • Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fdlers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, com starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or
  • compositions of the present invention can also be used to formulate the compositions of the present invention.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone, and the like.
  • Formulations for topical administration of nucleic acids can include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases.
  • the solutions can also contain buffers, diluents, and other suitable additives.
  • Pharmaceutically acceptable organic or inorganic excipients suitable for non- parenteral administration which do not deleteriously react with nucleic acids can be used.
  • the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months, or a year; or longer.
  • the pharmaceutical composition can be administered once daily, or administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation.
  • the nucleic acid e.g., siRNA contained in each sub- dose must be correspondingly smaller in order to achieve the total daily dosage.
  • the dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the nucleic acid e.g., siRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention.
  • the dosage unit contains a corresponding multiple of the daily dose.
  • Contacting of a cell with the inhibitor e.g., the nucleic acid e.g., an siRNA, such as a double stranded siRNA agent may be done in vitro or in vivo.
  • Contacting a cell in vivo with the inhibitor nucleic acid e.g., siRNA includes contacting a cell or group of cells within a subject, e.g., a human subject, with the nucleic acid e.g., siRNA. Combinations of in vitro and in vivo methods of contacting a cell are also possible. Contacting a cell may be direct or indirect, as discussed above.
  • inhibitor As used herein, is used interchangeably with “reducing,” “silencing,” “downregulating”, “suppressing”, and other similar terms, and includes any level of inhibition.
  • the nucleic acid of the invention when transfected into the cells, inhibits expression of the NR3C2 gene with an pEC50 value lower than 5, 6, 7, 8, 9 or 10, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein.
  • RT reverse transcriptase
  • the mean relative expression ofNR3C2 is below 1, 0.9, 0.8, 0.7, 0.6, 0.5, or 0.4, preferably when determined by qPCR, more preferably by reverse transcriptase (RT)-qPCR, as described herein.
  • Inhibition of expression of the NR3C2 gene may be quantified by the following method:
  • Cells may be transfected with siRNA duplexes targeting either NR3C2 mRNA or a negative control siRNA (siRNA-control; sense strand 5’- GCCTGTACCAAGGCTTTAA-3’ (SEQ ID NO: 1117), antisense strand 5’- TTAAAGCCTTGGTACAGGC-3 ’ (SEQ ID NO: 1118)) in a 6-point, log dose response curve to give final in assay concentrations of 3nM to 0.03pM. Transfection may be carried out by diluting Lipofectamine RNAi MAX (ThermoFisher) in Opti-MEM (ThermoFisher) medium at a ratio of 48.5: 1.5.
  • siRNAi MAX ThermoFisher
  • Opti-MEM ThermoFisher
  • Intracellular RNA may be isolated using a RNeasy kit (Qiagen) according to the manufacturer’s instructions.
  • cDNA synthesis may be performed using a HiScript III RT SuperMix kit (Vazyme) according to the manufacturer’s instructions.
  • Target cDNA may be quantified by qPCR on an ABI Prism 7900HT or ABI QuantStudio 7 with primers specific for human NR3C2 and human GAPDH (forward: GAAGGTGAAGGTCGGAGTC (SEQ ID NO: 1119), reverse: GAAGATGGTGATGGGATTTC (SEQ ID NO: 1120)) using an AceQ Universal U+ Probe Master Mix (Vazyme).
  • qPCR may be performed in duplicate on cDNA derived from each well and the mean Ct calculated.
  • Relative NR3C2 expression may be calculated from mean Ct values using the comparative Ct (AACt) method, normalized to GAPDH and relative to untreated cells.
  • Maximum percent inhibition of NR3C2 expression and EC50 and/or pEC50 values (-loglO of the EC50) may be calculated using a four parameter (variable slope) model using NumPy (Python).
  • Inhibition of the expression of a gene may be manifested by a reduction of the amount of mRNA of the target gene of interest in comparison to a suitable control.
  • Inhibition of the function of a target may be manifested by a reduction of the activity of the target in comparison to a suitable control.
  • inhibition of the expression of a gene or other target may be assessed in terms of a reduction of a parameter that is functionally linked to gene expression, e.g., protein expression or signalling pathways.
  • the present invention also provides methods of using nucleic acid e. g. , an siRNA of the invention or a composition containing nucleic acid e.g., an siRNA of the invention to reduce or inhibit gene expression in a cell or reduce expression or function of a target.
  • the methods include contacting the cell with a nucleic acid e.g., dsiRNA of the invention and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of a gene, thereby inhibiting expression of the gene in the cell.
  • Reduction in gene expression or function of a target can be assessed by any methods known in the art.
  • the gene is NR3C2.
  • a cell suitable for treatment using the methods of the invention may be any cell that expresses a gene of interest or target of interest associated with disease.
  • the in vivo methods of the invention may include administering to a subject a composition containing a nucleic acid of the invention e.g., an iRNA, where the nucleic acid e.g., siRNA includes a nucleoside sequence that is complementary to at least a part of an RNA transcript of the gene of the mammal to be treated, or complementary to another nucleic acid the expression and /or function of which is associated with diseases.
  • a nucleic acid of the invention e.g., an iRNA
  • siRNA includes a nucleoside sequence that is complementary to at least a part of an RNA transcript of the gene of the mammal to be treated, or complementary to another nucleic acid the expression and /or function of which is associated with diseases.
  • the present invention further provides methods of treatment of a subject in need thereof.
  • the treatment methods of the invention include administering a nucleic acid such as an siRNA of the invention to a subject, e.g., a subject that would benefit from a reduction or inhibition of the expression of a gene and/or expression and/or function of a target, in a therapeutically effective amount e.g., a nucleic acid such as an siRNA targeting a gene or a pharmaceutical composition comprising the nucleic acid targeting a gene.
  • the present invention further provides methods of treatment of a subject in need thereof.
  • the treatment methods of the invention include administering a nucleic acid such as an siRNA of the invention to a subject, e.g., a subject that would benefit from a reduction or inhibition of the expression of NR3C2 gene, in a therapeutically effective amount e.g., a nucleic acid such as an siRNA targeting NR3C2 or a pharmaceutical composition comprising the nucleic acid targeting NR3C2.
  • the disease to be treated is related to ischaemic heart diseases, in particular myocardial infarction, and/or symptoms thereof, HFrEF and/or symptoms thereof, and/or HFpEF and/or symptoms thereof.
  • the invention pertains to treatment of HFrEF and/or HFpEF.
  • Any reference herein to a disease including ischaemic heart disease, can equally be considered reference to HFrEF and/or HFpEF where allowed by context.
  • the nucleic acid according to the invention may be used in the prevention and/or treatment of an ischaemic heart disease.
  • ischaemic heart disease means any disorder resulting from an imbalance between the myocardial need for oxygen and the adequacy of the oxygen supply. Most cases of ischemic heart disease result from narrowing of the coronary arteries, as occurs in atherosclerosis or other vascular disorders.
  • the nucleic acid of the invention additionally may be useful for treating ischaemic damage to other organs.
  • Non-limiting examples of ischemic heart diseases include ischemic cardiomyopathy, myocardial infarction or ischemic heart failure and chronic ischemic heart disease.
  • the patient to be treated may be a patient that already has an ischaemic heart disease or that is at risk of developing an ischaemic heart disease. That is, in certain embodiments, the nucleic acid of the present invention may be used in the treatment of an existing ischaemic heart disease. Treatment of an existing ischaemic heart disease with the nucleic acid of the present invention may prevent worsening of the ischaemic heart disease and/or ischaemic heart disease. In some instances, treatment of an existing ischaemic heart disease with the nucleic acid of the present invention may even cure the ischaemic heart disease. In certain embodiments, the nucleic acid of the present invention may be used to prevent manifestation of an ischaemic heart disease in a patient that is at risk of developing an ischaemic heart disease.
  • Diagnosing an ischaemic heart disease may include medical history analysis, physical examination, imaging tests (such as ECG or stress test), blood tests (e.g., cardiac enzymes), and/or coronary angiography.
  • the ischaemic heart disease is myocardial infarction.
  • myocardial infarction means a process by which ischemic disease results in a region of the myocardium being replaced by scar tissue.
  • the coupling time was 180 seconds.
  • the oxidizer contact time was set to 80 seconds and thiolation time was 2* 100 seconds.
  • RNA phosphoramidites were purchased from ChemGenes or Hongene.
  • the 2'-O-Methyl phosphoramidites used were the following: 5'-(4,4'-dimethoxytrityl)-N- benzoyl-adenosine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'- dimethoxytrityl)-N-acetyl-cytidine 2'-O-methyl-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-(4,4'-dimethoxytrityl)-N-isobutyryl-guanosine 2'-O-methyl-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite, 5'-(4,4'-dimethoxytrityl)-uridine
  • the 2’-F phosphoramidites used were the following: 5'-dimethoxytrityl-N-benzoyl- deoxyadenosine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'-dimethoxytrityl-N- acetyl-deoxycytidine 2'-fluoro-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5'- dimethoxytrityl-N-isobutyryl-deoxyguanosine 2'-fluoro-3'- [(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite and 5'-dimethoxytrityl-deoxyuridine 2'-fhioro-3'-[(2-cyanoethyl)-(
  • the single strand oligonucleotides were purified by IP-RP HPLC on Xbridge BEH Cl 8 5 pm, 130 A, 19x150 mm (Waters) column with an increasing gradient of B in A.
  • Mobile phase A 240 mM HFIP, 7 mM TEA and 5% methanol in water
  • mobile phase B 240 mM HFIP, 7 mM TEA in methanol.
  • Sense strands were conjugated as per protocol provided in any of Examples 2, 4, 6.
  • Sense and Antisense strands were then annealed in water to form the final duplex siRNA and duplex purity were assessed by size exclusion chromatography.
  • SEQ ID NO: 1 to 223 refer to human (Homo sapiens) mRNA sequences.
  • Table 2 provides the unmodified first (antisense) and corresponding unmodified second (sense) strand sequences for siRNA oligonucleosides according to the present invention, together with the corresponding positions in the overall gene sequence of SEQ ID NO: 1116 as follows.
  • the invention relates to a nucleic acid comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following first and second sequences: [0555] In a further, particularly preferred, embodiment, the invention relates to a nucleic acid comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following first and second sequences:
  • EXAMPLE 9 DOSE-RESPONSE FOR INHIBITION OF NR3C2 EXPRESSION IN HUMAN HEK293 CELLS
  • siRNA duplexes targeting either NR3C2 mRNA or a negative control siRNA (siRNA-control; sense strand 5’- GCCTGTACCAAGGCTTTAA-3 ’ (SEQ ID NO: 1117), antisense strand 5’- TTAAAGCCTTGGTACAGGC-3’ (SEQ ID NO: 1118)) in a 6- point, log dose response curve to give final in assay concentrations of 3nM to 0.03pM.
  • Transfection was carried out by diluting Lipofectamine RNAiMAX (ThermoFisher) in Opti-MEM (ThermoFisher) medium at a ratio of 48.5: 1.5.
  • qPCR was performed in duplicate on cDNA derived from each well and the mean Ct calculated.
  • Relative NR3C2 expression was calculated from mean Ct values using the comparative Ct (AACt) method, normalized to GAPDH and relative to untreated cells.
  • Maximum percent inhibition of NR3C2 expression and pEC50 values are calculated using a four parameter (variable slope) model using NumPy (Python). Results are shown in Table 6. Sequences of RNAi molecules are depicted in the relevant Tables herein.
  • EXAMPLE 10 PREDICTION OF NR3C2 INHIBITION BY NUCLEIC ACIDS OF THE INVENTION
  • siRNAdesignR checked for cross species reactivity of the ranked siRNA sequences. This was not applied as a hard filter, but rather siRNA sequences would be preferred if they had cross species reactivity with Macaca fascicularis, Mus musculus and Rattus norvegicus but accepted if they had high efficacy predictions and Macaca fascicularis cross reactivity.
  • Figure 11 Highlighted in Figure 11 is an siRNA sequence that ranked within the top 20 predictions by siRNAdesignR for the target SLC25A5. This sequence was subsequently tested in dose response in vitro (in a Huh7 cell line), measuring the amount of mRNA knockdown (Figure 12), and in vivo (in C57BL/6 mice), measuring mRNA and protein knockdown ( Figures 13 and 14).
  • liver samples were homogenized, RNA was extracted using the MagMAXTM mirVanaTM Total RNA Isolation Kit (Thermo- A27828), cDNA was prepared using HiScript® III RT SuperMix for qPCR (+gDNA wiper)(Vazyme- R323), and gene expression of Nr3c2 and the housekeeper Gapdh were measured by RT-qPCR on a Q7 Fast Real-time PCR system (Applied biosystem).
  • Nr3c2 The levels of Nr3c2 were measured using in-house designed primers (Fwd: TCTGGCTTCTGCTTCTTC (SEQ ID NO: 1121); Rev: CTTCCAAGAGCAAGTTCTG (SEQ ID NO: 1122); Probe: AAGGACAGCACTCTCAGGACC (SEQ ID NO: 1123)) and Gapdh levels were measured using a commercial Taqman assay (Thermo, Mm99999915_g I ). The Expression levels were calculated using the 2-ddCt method whereby Nr3c2 levels were normalised to Gapdh levels and then normalised to the expression levels of vehicle control animals at each timepoint. The results are shown in Figure 20.
  • Nr3c2 The levels of Nr3c2 were measured using in-house designed primers (Fwd: TCTGGCTTCTGCTTCTTC (SEQ ID NO: 1121); Rev: CTTCCAAGAGCAAGTTCTG (SEQ ID NO: 1122); Probe: AAGGACAGCACTCTCAGGACC (SEQ ID NO: 1123)) and Gapdh levels were measured using a commercial Taqman assay (Thermo, Mm99999915 g 1 ). Expression levels were calculated using the 2 ddct method whereby Nr3c2 levels were normalised to Gapdh levels and then normalised to the expression levels of the vehicle control group. The results are shown in Figure 22A. [0586] Serum FGF21 levels were measured using a commercial ELISA kit (abeam ab212160), according to the manufacturer’s instructions. The results are shown in Figure 22B.
  • mice were injected weekly with saline or GalNAc-siRNA (ETX-M2590) starting on day -7 or day 0 (day of MI).
  • a positive control group received an MRA (Eplerenone) by food starting on day 0.
  • An additional group received weekly GalNAc-siRNA injections starting on day 0, combined with MRA treatment for the first 7 days post-MI.
  • Mice underwent Mi-induction on day 0 and survival, body weights and food intake were recorded throughout the study. A - Survival rates; B - Body weights; C - Food intake.
  • Systolic posterior wall thinning was observed in the MI group which was significantly improved with ETX- M2590 treatment pre- and post-MI as well as combination of ETX-M2590+MRA and by the positive control MRA alone (Figure 24G), indicating a potentially improved cardiac structural remodelling with ETX-M2590 treatment to reduce hepatic Nr3c2 expression. Diastolic posterior wall thickness was unaffected ( Figure 24H). Left ventricular mass was increased by MI, as expected, and not affected by treatment (Figure 51) and heart rate was not affected by any intervention (Figure 24J).
  • mice received 30 pg/mouse of a plasmid (pcDNA3. 1) encoding the human NR3C2 cDNA by hydrodynamic injection.
  • pcDNA3. 1 a plasmid encoding the human NR3C2 cDNA by hydrodynamic injection.
  • the animals were sacrificed, and livers were harvested.
  • NR3C2 Fwd: TGTATGAACTATGCCAGGGGA - SEQ ID NO: 1126; Rev: TGGAATTGTGCTTAGTAGCAGC - SEQ ID NO: 1127; Probe: CACCAAATCAGCCTTCAGTTCGTTCG - SEQ ID NO: 1128) and NEO (Fwd: GATGGATTGCACGCAGGTTCTC - SEQ ID NO: 1128; Rev: GAACACGGCGGCATCAGAGC - SEQ ID NO: 1130; Probe: CGCTTGGGTGGAGAGGCTATTCGGCTATGA - SEQ ID NO: 1131). Expression levels were calculated using the 2 -ddct method whereby NR3C2 levels were normalised to NEO levels and then normalised to the expression levels in saline-injected controls.
  • hepatic expression of the human NR3C2 transcript in mice was achieved by injecting 30 pg of a plasmid (pcDNA3.1) encoding the human NR3C2 cDNA into mice via hydrodynamic injection. Mice were injected with 3 mg/kg of the respective GalNAc- siRNAs six days before HDI and were sacrificed one day post-HDI to assess hepatic expression of human NR3C2 and the internal expression control neomycin resistance (NEO).
  • pcDNA3.1 plasmid encoding the human NR3C2 cDNA
  • mice were injected with saline, a negative control GalNAc-siRNA with no target mRNA in mouse, as well as 15 different anti-NR3C2 GalNAc-siRNAs on day -6.
  • Mice were injected by hydrodynamic injection (HDI) with an NR3C2 encoding plasmid on day 0 and sacrificed on day 1.
  • Livers were collected and human NR3C2 target mRNA levels were analysed by qPCR and normalised to the expression control NEO.
  • A Hepatic target mRNA levels following injection with 3 mg/kg GalNAc- siRNA, negative control GalNAc-siRNA or saline.
  • PHH cells from BioIVT & Elevating ScienceTM were cultured in InvitroGRO CP Medium (BioreclamationIVT-S03316, 225 mL) supplemented with Fetal bovine serum (Gbico-10091148, 25.3 mL) and Penicillin- Streptomycin Solution (Gibco- 15070-063, 2.5 mL).
  • GalNAc-siRNA were transfected using Lipofectamine®RNAiMAX Reagent (ThermoFisher) at 0.0 InM and l.OnM for 48 hours.
  • siRNAs tested in this study are shown in Table 8 below along with their Mean Relative Expression. Activity of all tested siRNAs is shown in Figure 26. All tested siRNAs displayed activity in PHH. Results were evaluated with the HDI results (Example 15) to select lead siRNAs. Table 8
  • EXAMPLE 15 Confirmation of siRNA Activity in a Human hydrodynamic injection (HDD Mouse Model
  • pcDNA3.1 a plasmid
  • qPCR was performed in triplicate on cDNA derived from each well and the mean Ct calculated.
  • Relative NR3C2 expression was calculated from mean Ct values using the comparative Ct (AACt) method, normalised to NEO and relative to vehicle-injected.
  • siRNAs tested in this study are shown in Table 9 below along with their mean relative expression in the experiment. Activity of all tested siRNAs was in the human HDI mouse model is shown in Figure 28. As can be seen from Figure 28 and Table 9, a number of siRNAs tested displayed high activity against the human NR3C2 mRNA sequence. Particularly preferred siRNAs for use in the invention are ETX-M00003139 and ETX-M00003137, and these are specifically contemplated through this disclosure, even when not singled out in a specific passage of this disclosure.
  • EXAMPLE 16 DISEASE MODEL PROOF-OF-CONCEPT (PoC) STUDY - HFpEF
  • HFpEF was induced in C57B6N mice fed a high-fat diet (60% kcal from fat) and water containing L-NAME (0.5 g/L) over 11 weeks. Mice were randomized into homogenous treatment groups, according to their echocardiography parameters obtained at week 10 (E/A ratio, E7A’ ratio and ejection fraction confirming HFpEF phenotype) after the induction phase. One group of mice was treated with 10 mg/kg ETX-M00002590 weekly for 6 weeks by subcutaneous injection. Control animals received weekly subcutaneous saline injections.
  • Positive control groups received either eplerenone in their diet (Ig/kg diet) or 10 mg/kg empagliflozin by daily oral gavage for a period of 6 weeks (until end of study). All groups remained on a high fat diet and L-NAME drinking water for the duration of the study.
  • left ventricular function and dimensions was assessed using two-dimensional echocardiograph (VF16-5 probe, Siemens, Acuson NX3 Elite). Numeric images of the heart were obtained in parasternal long and short-axis views using or not time motion for systolic function. Heart rate left ventricular end-diastolic and end-systolic diameters and volumes, as well as posterior and anterior wall thicknesses in diastole and systole were measured. Left ventricular ejection fraction and fractional shortening were calculated. Diastolic function was assessed using pulse-wave doppler imaging from apical four chambers view of the mitral flow and the mitral annulus.
  • VF16-5 probe Siemens, Acuson NX3 Elite
  • IVRT isovolumic relaxation time
  • annular tissue velocity of the mitral valve E’ and A’ peaks
  • Echocardiography examination in week 17 showed a cardiac remodelling in HFD/L-NAME vehicle mice, with an increase in Left Ventricle (LV) wall thickness, as assessed by anterior and posterior wall thickness in diastole and systole.
  • LV anterior and posterior wall thickness in diastole and systole were improved by treatment with ETX-M00002590 ( Figure 30).
  • Eplerenone also led to statistically significant improvements in all four parameters.
  • ETX-M00002590 treatment achieved beneficial effects on improved diastolic function, while reducing cardiac hypertrophy, arterial pressure, and LV end-diastolic pressure in HFD / L-NAME induced model of HFpEF.
  • an inhibitor, or inhibitor for use, according to one or more preceding clauses which is an siRNA oligomer having a first and a second strand wherein: i) the first strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 23 or 25; even more preferably 23; and / or ii) the second strand of the siRNA has a length in the range of 15 to 30 nucleosides, preferably 19 to 25 nucleosides, more preferably 21 nucleosides.
  • the reversed linkage is a 5-5’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 3’5’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides; or (2) the reversed linkage is a 3-3’ reversed linkage and the linkage between the terminal and penultimate abasic nucleosides is 5’3’ when reading towards the terminus comprising the terminal and penultimate abasic nucleosides.
  • Xi and X 2 at each occurrence are independently selected from the group consisting of methylene, oxygen and sulfur; m is an integer of from 1 to 6; n is an integer of from 1 to 10; q, r, s, t, v are independently integers from 0 to 4, with the proviso that:
  • Z is an oligomer
  • a pharmaceutical composition comprising an inhibitor according to one or more preceding clauses, in combination with a pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition comprising an inhibitor according to one or more preceding clauses, in combination with a pharmaceutically acceptable excipient or carrier, for use in the treatment of HFrEF, such as an ischaemic heart disease, in particular myocardial infarction and/or symptoms thereof, and/or for use in the treatment of HFpEF and/or symptoms thereof.
  • HFrEF such as an ischaemic heart disease, in particular myocardial infarction and/or symptoms thereof, and/or for use in the treatment of HFpEF and/or symptoms thereof.
  • a method of predicting susceptibility to HFrEF such as an ischaemic heart disease, in particular myocardial infarction and/or symptoms thereof, and/or predicting susceptibility to HFpEF and/or symptoms thereof, and optionally treating a disease related to HFrEF, such as an ischaemic heart disease, in particular myocardial infarction and/or symptoms thereof, and/or a disease related to HFpEF and/or symptoms thereof in a patient, said method comprising:
  • (ii) comprises at least 17 contiguous nucleosides differing by 0 or 1 nucleosides from any one of the first strand sequences as listed in Table 2.
  • a nucleic acid according to clause 50, wherein the first strand comprises any one of the following sequences: SEQ ID NO: 228, SEQ ID NO: 238, SEQ ID NO: 243, SEQ ID NO: 235, SEQ ID NO: 245 and SEQ ID NO: 250, preferably SEQ ID NO: 238 or SEQ ID NO: 245.
  • a nucleic acid according to clause 45 or clause 48 comprising first and second strands that comprise, consist of, or consist essentially of a nucleoside sequence differing by 0 or 1 nucleosides from any one of the following combinations of first and second sequences:

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Abstract

La présente invention concerne des inhibiteurs, et des compositions contenant des inhibiteurs, et leurs utilisations dans le traitement ou la prévention d'une maladie, d'un trouble ou d'un état lié à HFrEF, tel qu'une cardiopathie ischémique, et/ou HFpEF.
PCT/EP2025/058565 2024-03-29 2025-03-28 Inhibiteurs d'expression et/ou de fonction Pending WO2025202455A2 (fr)

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EP3775207A1 (fr) 2018-04-05 2021-02-17 Silence Therapeutics GmbH Siarns avec vinylphosphonate à l'extrémité 5' du brin antisens
WO2023059948A1 (fr) 2021-10-08 2023-04-13 E-Therapeutics Plc Acides nucléiques contenant des nucléosides abasiques

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WO2006002022A2 (fr) * 2004-06-15 2006-01-05 Immusol Incorporated Compositions et methodes utiles pour le traitement de l'hyperglycemie
WO2022162161A1 (fr) * 2021-01-30 2022-08-04 E-Therapeutics Plc Composés oligonucléotidiques conjugués, leurs procédés de fabrication et leurs utilisations
JP2025519286A (ja) * 2022-06-01 2025-06-25 イー－セラピューティクス・ピーエルシー 発現および／または機能の阻害剤
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EP3775207A1 (fr) 2018-04-05 2021-02-17 Silence Therapeutics GmbH Siarns avec vinylphosphonate à l'extrémité 5' du brin antisens
WO2023059948A1 (fr) 2021-10-08 2023-04-13 E-Therapeutics Plc Acides nucléiques contenant des nucléosides abasiques

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