COMPOSITIONS AND METHODS FOR INHIBITING MARC1 GENE EXPRESSION

1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a MARC1 gene, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence comprising at least 15, 17, 19, or 21 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, from one of the antisense sequences listed in Table 2A 2B, 3A, 3B, 4A, or 4B.

2 . The dsRNA agent of claim 1 , wherein the sense strand comprises a nucleotide sequence comprising at least 15, 17, 19, or 21 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, from a sense sequence listed in Table 2A, 2B, 3A, 3B, 4A, or 4B that corresponds to the antisense sequence.

3 . The dsRNA agent of claim 1 or 2 , wherein the dsRNA agent comprises at least one modified nucleotide.

4 . The dsRNA agent of claim 3 , wherein no more than five of the sense strand nucleotides and not more than five of the nucleotides of the antisense strand are unmodified nucleotides.

5 . The dsRNA agent of claim 3 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification.

6 . The dsRNA agent of any one of claims 3 - 5 , wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a glycol modified nucleotide, and a 2-O—(N-methylacetamide) modified nucleotide; and combinations thereof.

7 . The dsRNA agent of any of the preceding claims, further comprising a ligand.

8 . The dsRNA agent of claim 7 , wherein the ligand is conjugated to the sense strand.

9 . The dsRNA agent of claim 7 or 8 , wherein the ligand is conjugated to the 3′ end or the 5′ end of the sense strand.

10 . The dsRNA agent of claim 7 or 8 , wherein the dsRNA agent is conjugated to the 3′ end of the sense strand.

11 . The dsRNA agent of any one of claims 7 - 10 , wherein the ligand comprises N-acetylgalactosamine (GalNAc).

12 . The dsRNA agent of any one of claims 7 - 11 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

13 . The dsRNA agent of claim 12 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent linker, or a bivalent, trivalent, or tetravalent branched linker.

14 . The dsRNA agent of claim 12 , wherein the ligand is

15 . The dsRNA agent of claim 14 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

16 . The dsRNA agent of claim 15 , wherein the X is O.

17 . The dsRNA agent of any of the preceding claims, wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides.

18 . The dsRNA agent of any of the preceding claims, wherein the double stranded region is 15-30 nucleotide pairs in length.

19 . The dsRNA agent of claim 18 , wherein the double stranded region is 17-23 nucleotide pairs in length.

20 . The dsRNA agent of any of the preceding claims, wherein each strand has 19-30 nucleotides.

21 . The dsRNA agent of any of the preceding claims, wherein the agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

22 . A cell containing the dsRNA agent of any one of claims 1 - 21 .

23 . A pharmaceutical composition for inhibiting expression of a MARC1 gene, comprising the dsRNA agent of any one of claims 1 - 21 .

24 . A method of inhibiting expression of a MARC1 gene in a cell, the method comprising:

(a) contacting the cell with the dsRNA agent of any one of claims 1 - 21 , or a pharmaceutical composition of claim 23 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to reduce levels of MARC1 mRNA, MARC1 protein, or both of MARC1 mRNA and protein, thereby inhibiting expression of the MARC1 gene in the cell.

25 . The method of claim 24 , wherein the cell is within a subject.

26 . The method of claim 25 , wherein the subject is a human.

27 . The method of claim 26 , wherein the subject has been diagnosed with a metabolic disorder or hepatic fibrosis.

28 . The method of claim 27 , wherein the metabolic disorder is nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

29 . A method of treating a subject having or diagnosed with having a MARC1-associated disorder comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1 - 21 or a pharmaceutical composition of claim 23 , thereby treating the disorder.

30 . The method of claim 29 , wherein the MARC1-associated disorder is a metabolic disorder (e.g., nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)) or hepatic fibrosis.

31 . A method of reducing serum cholesterol levels (e.g., total cholesterol levels, or LDL cholesterol levels) in a subject, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of any one of claims 1 - 21 or a pharmaceutical composition of claim 23 , thereby reducing serum cholesterol levels.

32 . The method of any one of claims 25 - 31 , wherein the dsRNA agent is administered to the subject intravenously.