Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.
1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1395 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification,
wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.
2. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1394 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification,
wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.
3. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Angiopoietin-like 3 (ANGPTL3), comprising a sense strand and an antisense strand forming a duplex region,
wherein the antisense strand comprises at least 17 contiguous nucleotides which differ by no more than three nucleotides from nucleotides 1354-1385 of SEQ ID NO:1,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification,
wherein at least one of the nucleotide modifications is selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a nucleotide comprising a 5′-phosphorothioate group modification, and
wherein a ligand comprising an N-acetylgalactosamine (GalNAc) is conjugated to at least one strand of the dsRNA agent.
4. The dsRNA agent of claim 1 , wherein each strand is independently 19-25 nucleotides in length.
5. The dsRNA agent of claim 1 , wherein the duplex region is 15-30 base pairs in length.
6. The dsRNA agent of claim 1 , wherein the duplex region is 18-21 base pairs in length.
7. The dsRNA agent of claim 1 , wherein the duplex region is 20 base pairs in length.
8. The dsRNA agent of claim 1 , wherein the dsRNA agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
9. The dsRNA of claim 1 , wherein the GalNAc (N-acetylgalactosamine) is conjugated to at least one strand of the dsRNA agent through a linker.
10. The dsRNA of claim 9 , wherein the GalNAc (N-acetylgalactosamine) is conjugated through a bivalent or trivalent branched linker.
11. The dsRNA of claim 9 , wherein the linker comprises C(O)NH.
12. The dsRNA of claim 11 , wherein the linker comprises between 1-24 atoms.
13. The dsRNA of claim 11 , wherein the linker comprises between 6-24 atoms.
14. The dsRNA agent of claim 1 , wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of
5′-UACUCUAUAAAAUCAACCAAAA-3′ (SEQ ID NO: 1182) and 5′-UUUGGUUGAUUUUAUAGAGUAUA-3′(SEQ ID NO: 1363);
5′-AUACUCUAUAAAAUCAACCAA-3′ (SEQ ID NO: 1177) and 5′-UUGGUUGAUUUUAUAGAGUAUAA-3′ (SEQ ID NO: 1358);
5′-AUGGAAGGUUAUACUCUAUAA-3′ (SEQ ID NO: 1166) and 5′-UUAUAGAGUAUAACCUUCCAUUU-3′ (SEQ ID NO: 1347);
5′-UGGAAGGUUAUACUCUAUAAA-3′ (SEQ ID NO: 1172) and 5′-UUUAUAGAGUAUAACCUUCCAUU-3′ (SEQ ID NO: 1353); and
5′-GUCUCAAAAUGGAAGGUUAUA-3′ (SEQ ID NO: 1160) and 5′-UAUAACCUUCCAUUUUGAGACUU-3′ (SEQ ID NO: 1341).
15. An isolated cell containing the dsRNA agent of claim 1 .
16. A pharmaceutical composition for inhibiting expression of an ANGPTL3 gene, comprising the dsRNA agent of claim 1 .
17. The pharmaceutical composition of claim 16 , wherein the dsRNA agent is present in a buffered solution.
18. A method of inhibiting ANGPTL3 expression in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of claim 1 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of an ANGPTL3 gene, thereby inhibiting expression of the ANGPTL3 gene in the cell.
19. The method of claim 18 , wherein the cell is within a subject.
20. A method of inhibiting the expression of ANGPTL3 in a subject, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby inhibiting the expression of ANGPTL3 in the subject.
21. A method of treating a subject having a disorder that would benefit from reduction in ANGPTL3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent of claim 1 , thereby treating the subject.
22. The method of claim 21 , wherein the disorder is a disorder of lipid metabolism.
23. The method of claim 21 , wherein the disorder is selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, atherosclerosis, diabetes, cardiovascular disease, and coronary artery disease.
24. The method of claim 23 , wherein the disorder is hyperlipidemia.
25. The method of claim 21 , further comprising administering an additional therapeutic to the subject.
26. The method of claim 25 , wherein the additional therapeutic is a statin.
27. The method of claim 21 , wherein the administration of the dsRNA agent to the subject causes a decrease in one or more serum lipid.
28. The method of claim 21 , wherein the administration of the dsRNA agent to the subject causes a decrease in ANGPTL3 protein accumulation.
29. The method of claim 21 , wherein the subject is a human subject.