Serum amyloid P component (APCS) iRNA compositions and methods of use thereof
The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the serum amyloid P component (APCS) gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of an APCS gene and to treat subjects having an APCS-associated disease, e.g., amyloidosis, Alzheimer's disease or coronary atherosclerotic heart disease.
1. A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a serum amyloid P component (APCS) gene, comprising a sense strand and an antisense strand forming a double stranded region, wherein said antisense strand comprises the nucleotide sequence 5′-UAAGUUUACAUGAUCAGUAACAG-3′ (SEO ID NO:103).
2. The double stranded RNAi agent of claim 1 , wherein said RNAi agent comprises at least one modified nucleotide.
3. The double stranded RNAi agent of claim 2 , wherein at least one of said 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′-hydroxly-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a 5′-vinyl phosphate, 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, and a nucleotide comprising a 5′-phosphate mimic.
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; each strand is independently 19-30 nucleotides in length; or each strand is independently 19-25 nucleotides in length.
6. The double stranded RNAi agent of claim 5 , wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.
7. 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.
8. The double stranded RNAi agent of claim 1 , further comprising a ligand.
9. The double stranded RNAi agent of claim 8 , wherein the ligand is conjugated to the 3′ end of the sense strand of the double stranded RNAi agent.
10. The double stranded RNAi agent of claim 8 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
11. The double stranded RNAi agent of claim 10 , wherein the ligand is
12. The double stranded RNAi agent of claim 11 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic
and wherein X is O or S.
13. The double stranded RNAi agent of claim 12 , wherein the X is O.
14. A cell containing the double stranded RNAi agent of claim 1 .
15. A pharmaceutical composition for inhibiting expression of a serum amyloid P component (APCS) gene comprising the double stranded RNAi agent of claim 1 .
16. The double stranded RNAi agent of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-GUUACUGAUCAUGUAAACUUA-3′ (SEQ ID NO:19) and the antisense strand comprises the nucleotide sequence 5′-UAAGUUUACAUGAUCAGUAACAG-3′ (SEQ ID NO:103).
17. The double stranded RNAi agent of claim 1 , wherein the antisense strand comprises the modified nucleotide sequence 5′-VPusAfsaguUfuAfCfaugaUfcAfguaacsasg-3′ (SEQ ID NO:271).
18. The double stranded RNAi agent of claim 16 , wherein the sense strand comprises the nucleotide sequence 5′-gsusuacuGfaUfCfAfuguaaacuuaL96-3′ (SEQ ID NO:187) and the antisense strand comprises the nucleotide sequence 5′-VPusAfsaguUfuAfCfaugaUfcAfguaacsasg-3′ (SEQ ID NO:271).
19. A method of inhibiting expression of a serum amyloid P component (APCS) gene in a cell, the method comprising contacting the cell with the double stranded RNAi agent of claim 1 , thereby inhibiting expression of the APCS gene in the cell.
20. A method of inhibiting the expression of an APCS protein (SAP) in a subject, the method comprising
administering to said subject a therapeutically effective amount of the double stranded RNAi agent of claim 1 , thereby inhibiting the expression of APCS in said subject.
21. A double stranded ribonucleic acid (RNAi) agent for inhibiting expression of a serum amyloid P component (APCS) gene, comprising a sense strand and an antisense strand forming a double stranded region, wherein said antisense strand comprises the nucleotide sequence 5′-UAUACAGAUAGGAAAUUCAAAGA-3′ (SEQ ID NO:171).
22. The double stranded RNAi agent of claim 21 , wherein the sense strand comprises the nucleotide sequence 5′-UUUGAAUUUCCUAUCUGUAUA-3′ (SEQ ID NO:87) and the antisense strand comprises the nucleotide sequence 5′-UAUACAGAUAGGAAAUUCAAAGA-3′ (SEQ ID NO:171).
23. The double stranded RNAi agent of claim 21 , wherein the antisense strand comprises the modified nucleotide sequence 5′-VPusAfsuacAfgAfUfaggaAfaUfucaaasgsa-3′ (SEQ ID NO:339).
24. The double stranded RNAi agent of claim 22 , wherein the sense strand comprises the nucleotide sequence 5′-ususugaaUfuUfCfCfuaucuguauaL96-3′ (SEQ ID NO:255) and the antisense strand comprises the nucleotide sequence 5′-VPusAfsuacAfgAfUJfaggaAfaUfucaaasgsa-3′ (SEQ ID NO:339).
25. The double stranded RNAi agent of claim 21 , wherein said RNAi agent comprises at least one modified nucleotide.
26. The double stranded RNAi agent of claim 25 , wherein at least one of said 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′-hydroxly-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a 5′-vinyl phosphate, 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, and a nucleotide comprising a 5′-phosphate mimic.
27. The double stranded RNAi agent of claim 26 , further comprising at least one phosphorothioate internucleotide linkage.
28. The double stranded RNAi agent of claim 21 , wherein each strand is no more than 30 nucleotides in length; each strand is independently 19-30 nucleotides in length; or each strand is independently 19-25 nucleotides in length.
29. The double stranded RNAi agent of claim 28 , wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.
30. The double stranded RNAi agent of claim 21 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide; or a 3′ overhang of at least 2 nucleotides.
31. The double stranded RNAi agent of claim 21 , further comprising a ligand.
32. The double stranded RNAi agent of claim 31 , wherein the ligand is conjugated to the 3′ end of the sense strand of the double stranded RNAi agent.
33. The double stranded RNAi agent of claim 32 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
34. The double stranded RNAi agent of claim 33 , wherein the ligand is
35. The double stranded RNAi agent of claim 34 , wherein the double stranded RNAi agent is conjugated to the ligand as shown in the following schematic
and wherein X is O or S.
36. The double stranded RNAi agent of claim 35 , wherein the X is O.
37. A cell containing the double stranded RNAi agent of claim 21 .
38. A pharmaceutical composition for inhibiting expression of a serum amyloid P component (APCS) gene comprising the double stranded RNAi agent of claim 21 .
39. A method of inhibiting expression of a serum amyloid P component (APCS) gene in a cell, the method comprising contacting the cell with the double stranded RNAi agent of claim 21 , thereby inhibiting expression of the APCS gene in the cell.
40. A method of inhibiting the expression of an APCS protein (SAP) in a subject, the method comprising
administering to said subject a therapeutically effective amount of the double stranded RNAi agent of claim 21 , thereby inhibiting the expression of APCS in said subject.