Sterol regulatory element binding protein (SREBP) chaperone (SCAP) iRNA compositions and methods of use thereof
The invention relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting the SCAP gene, as well as methods of inhibiting expression of a SCAP gene and methods of treating subjects having a SCAP-associated disorder, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), using such dsRNAi agents and compositions.
1 . A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a sterol regulatory element binding protein (SREBP) chaperone (SCAP) gene, or a salt thereof,
wherein said dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises at least 15 contiguous nucleotides from the complement of nucleotides 1237-1277 of SEQ ID NO:2.
2 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein at least one nucleotide the double stranded RNAi agent, or a salt thereof, comprises a nucleotide modification.
3 . The double stranded RNAi agent, or a salt thereof, of claim 2 , wherein at least one of the nucleotide modification is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy--nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino--nucleotide modification, a 2′-O-allyl--nucleotide modification, 2′-C-alkyl--nucleotide modification, 2′-hydroxyl--nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl--nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a 5′-phosphorothioate group modification, a nucleotide comprising a 5′-methylphosphonate group modification, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic modification, a nucleotide comprising vinyl phosphate modification, a nucleotide comprising adenosine-glycol nucleic acid (GNA) modification, a nucleotide comprising thymidine-glycol nucleic acid (GNA) S-Isomer modification, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate modification, a nucleotide comprising 2′-deoxythymidine-3′phosphate modification, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate modification, and a terminal nucleotide linked to a cholesteryl derivative and a dodecanoic acid bisdecylamide group modification.
4 . The double stranded RNAi agent, or a salt thereof, of claim 2 , further comprising at least one phosphorothioate internucleotide linkage.
5 . The double stranded RNAi agent, or a salt thereof, of claim 1 , wherein each strand is no more than 30 nucleotides in length.
6 . The double stranded RNAi agent, or a salt thereof, 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, or a salt thereof, of claim 1 , wherein the double stranded RNAi agent further comprises a ligand.
8 . The double stranded RNAi agent, or a salt thereof, of claim 7 , wherein the ligand is
9 . The double stranded RNAi agent, or a salt thereof, 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.
10 . The double stranded RNAi agent, or a salt thereof, of claim 9 , wherein X is O.
11 . A cell containing the double stranded RNAi agent, or a salt thereof, of claim 1 .
12 . A pharmaceutical composition for inhibiting expression of a SCAP gene comprising the double stranded RNAi agent, or a salt thereof, of claim 1 .
13 . 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 a salt thereof; 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.
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 a salt thereof, 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 . The method of claim 14 , wherein the double stranded RNAi agent or a salt thereof, is administered to the subject subcutaneously.
19 . A kit for performing the method of claim 14 , comprising
a) the double stranded RNAi agent, or a salt thereof, and
b) instructions for use, and
c) optionally, means for administering the double stranded RNAi agent, or a salt thereof, to the subject.
20 . 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.
21 . The double stranded RNAi agent of claim 10 , wherein the 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′-UCCCACAGACAUGAGCAGC-3′ of SEQ ID NO:1230.
23 . The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UCAGAGUCCCACAGACAUG-3′ of SEQ ID NO:1232.
24 . The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-UCAGGCCGAAGAGUGUGCA-3′ of SEQ ID NO:1234.
25 . The double stranded RNAi agent of claim 22 , wherein the sense strand comprises the nucleotide sequence 5′-GCUGCUCAUGUCUGUGGGA-3′ of SEQ ID NO:1229 and the antisense strand comprises the nucleotide sequence 5′-UCCCACAGACAUGAGCAGC-3′ of SEQ ID NO:1230.
26 . The double stranded RNAi agent of claim 23 , wherein the sense strand comprises the nucleotide sequence 5′-CAUGUCUGUGGGACUCUGA-3′ of SEQ ID NO:1231 and the antisense strand comprises the nucleotide sequence 5′-UCAGAGUCCCACAGACAUG-3′ of SEQ ID NO:1232.
27 . The double stranded RNAi agent of claim 24 , wherein the sense strand comprises the nucleotide sequence 5′-UGCACACUCUUCGGCCUGA-3′ of SEQ ID NO:1233 and the antisense strand comprises the nucleotide sequence 5′-UCAGGCCGAAGAGUGUGCA-3′ of SEQ ID NO:1234.