Sterol regulatory element binding protein (SREBP) chaperone (SCAP) iRNA compositions and methods of use thereof

1. A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene,

wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

wherein said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the complement of nucleotides 4164-4211 of SEQ ID NO:1.

2. The double stranded RNAi agent of claim 1 , wherein the double stranded RNAi agent comprises at least one modified nucleotide.

3. The double stranded RNAi agent of claim 2 , 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, 2′-hydroxyl-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 5′-phosphorothioate group, a nucleotide comprising a 5′-methylphosphonate group, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic, a nucleotide comprising vinyl phosphate, a nucleotide comprising adenosine-glycol nucleic acid (GNA), a nucleotide comprising thymidine-glycol nucleic acid (GNA)S-Isomer, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate, a nucleotide comprising 2′-deoxythymidine-3′phosphate, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group.

4. The double stranded RNAi agent of claim 2 , further comprising at least one phosphorothioate internucleotide linkage.

5. The double stranded RNAi agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.

6. The double stranded RNAi agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides.

7. The double stranded RNAi agent of claim 1 , wherein the double stranded RNAi agent further comprises a ligand.

8. The double stranded RNAi agent of claim 7 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic

and, wherein X is O or S.

9. The double stranded RNAi agent of claim 7 , wherein the ligand is a cholesterol.

10. A cell containing the double stranded RNAi agent of claim 1 .

11. A pharmaceutical composition for inhibiting expression of a SCAP gene comprising the double stranded RNAi agent of claim 1 .

12. A method of inhibiting for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene in a cell, the method comprising:

(a) contacting the cell with the double stranded RNAi agent of claim 1 or the pharmaceutical composition of claim 11 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a SCAP gene, thereby inhibiting expression of the SCAP gene in the cell.

13. The method of claim 12 , wherein said cell is within a subject.

14. A method of treating a subject having a disorder that would benefit from a reduction in SCAP expression, comprising administering to the subject a therapeutically effective amount of the double stranded RNAi agent of claim 1 or the pharmaceutical composition of claim 11 , thereby treating said subject.

15. The method of claim 14 , wherein the subject suffers from a SCAP-associated disorder.

16. The method of claim 14 , wherein the subject is a human.

17. The method of claim 15 , wherein the SCAP-associated disease is nonalcoholic fatty liver disease (NAFLD); fatty liver (steatosis); nonalcoholic steatohepatitis (NASH).

18. A kit for performing the method of claim 14 , comprising

a) the double stranded RNAi agent of claim 1 , and

b) instructions for use, and

c) optionally, means for administering the double stranded RNAi agent to the subject.

19. The double stranded RNAi agent of claim 7 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative conjugated to the 3′ end of the sense strand through a monovalent or branched bivalent or trivalent linker.

20. The double stranded RNAi agent of claim 19 , wherein the ligand is

21. The double stranded RNAi agent of claim 3 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

22. The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-ACUCGGCUCUUUCCCCCAA-3′ (SEQ ID NO:1600).

23. The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UCAGCGGCUGGAAGAUACU-3′ (SEQ ID NO:1602).

24. The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UUACAGUCAGGAGGCAGCG-3′ (SEQ ID NO:1604).

25. The double stranded RNAi agent of claim 22 , wherein the sense strand comprises the nucleotide sequence 5′-UUGGGGGAAAGAGCCGAGU-3′ (SEQ ID NO:1599) and the antisense strand comprises the nucleotide sequence 5′-ACUCGGCUCUUUCCCCCAA-3′ (SEQ ID NO:1600).

26. The double stranded RNAi agent of claim 23 , wherein the sense strand comprises the nucleotide sequence 5′-AGUAUCUUCCAGCCGCUGA-3′ (SEQ ID NO:1601) and the antisense strand comprises the nucleotide sequence 5′-UCAGCGGCUGGAAGAUACU-3′ (SEQ ID NO:1602).

27. The double stranded RNAi agent of claim 24 , wherein the sense strand comprises the nucleotide sequence 5′-CGCUGCCUCCUGACUGUAA-3′ (SEQ ID NO:1603) and the antisense strand comprises the nucleotide sequence 5′-UUACAGUCAGGAGGCAGCG-3′ (SEQ ID NO:1604).

28. The method of claim 14 , further comprising administering an additional therapeutic agent to the subject.

29. The method of claim 14 , wherein the double stranded RNAi agent is administered at a dose of about 0.01 mg/kg to about 50 mg/kg.

30. The method of claim 14 , wherein the double stranded RNAi agent is administered to the subject subcutaneously.

31. The method of claim 14 , wherein the administration of the double stranded RNAi to the subject causes a decrease in one or more serum lipid and a decrease in SCAP protein accumulation; PNPLA3 protein accumulation; or SREBP double stranded RNAi accumulation.