Superoxide dismutase 1 (SOD1) iRNA compositions and methods of use thereof for treating or preventing superoxide dismutase 1-(SOD1-) associated neurodegenerative diseases
The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a SOD1 gene, as well as methods of inhibiting expression of a SOD1 gene and methods of treating subjects having a SOD1-associated neurodegenerative disease or disorder, e.g., Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS), using such dsRNAi agents and compositions.
1. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double stranded region, wherein the nucleotide sequence of the antisense strand differs by no more than three bases from the nucleotide sequence,
(SEQ ID NO: 1369)
5′-VPusdCsugdGadTagagdGaUfuaaagugsa-3′,
wherein
VP is a 5′-vinyl phosphonate;
s is a phosphorothioate linkage;
a, g, and u are 2′-O-methyl (2′-OMe) A, G, and U;
dC, dG, and dT are 2′-deoxy C, G, and T; and
Uf is 2′-deoxy-2′-fluoro (2′-F) U.
2. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand differs by no more than two bases from the nucleotide sequence
(SEQ ID NO: 1369)
5′-VPusdCsugdGadTagagdGaUfuaaagugsa-3′.
3. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand differs by no more than one base from the nucleotide sequence
(SEQ ID NO: 1369)
5′-VPusdCsugdGadTagagdGaUfuaaagugsa-3′.
4. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand comprises the nucleotide sequence
(SEQ ID NO: 1369)
5′-VPusdCsugdGadTagagdGaUfuaaagugsa-3′.
5. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-VPusdCsugdGadTagagdGaUfuaaagugsasg-3′ (SEQ ID NO:12).
6. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence,
(SEQ ID NO: 11)
5′-csascuu(Uhd)aaUfCfCfucuauccasgsa-3′
wherein
(Uhd) is 2′-O-hexadecyl-uridine-3′-phosphate;
c is 2′-O-methyl (2′-OMe) C; and
Cf is 2′-deoxy-2′-fluoro (2′-F) C.
7. The dsRNA agent of claim 6 , that is a sodium salt.
8. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises the nucleotide sequence,
(SEQ ID NO: 12)
5′-VPusdCsugdGadTagagdGaUfuaaagugsasg-3′.
9. The dsRNA agent of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the sense strand comprises the nucleotide sequence,
(SEQ ID NO: 11)
5′-csascuu(Uhd)aaUfCfCfucuauccasgsa-3′
wherein
(Uhd) is 2′-O-hexadecyl-uridine-3′-phosphate;
c is 2′-O-methyl (2′-OMe) C; and
Cf is 2′-deoxy-2′-fluoro (2′-F) C.
10. The dsRNA agent of claim 9 , that is a sodium salt.
11. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand consists of the nucleotide sequence,
(SEQ ID NO: 11)
5′-csascuu(Uhd)aaUfCfCfucuauccasgsa-3′
and the antisense strand consists of the nucleotide sequence,
(SEQ ID NO: 12)
5′-VPusdCsugdGadTagagdGaUfuaaagugsasg-3′,
wherein
VP is a 5′-E-vinyl phosphonate;
s is a phosphorothioate linkage;
(Uhd) is 2′-O-hexadecyl-uridine-3′-phosphate;
a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U;
dC, dG, and dT are 2′-deoxy C, G, and T; and
Cf and Uf are 2′-deoxy-2′-fluoro (2′-F) C and U.
12. The dsRNA agent of claim 11 , that is a sodium salt.
13. A pharmaceutical composition comprising the dsRNA agent of claim 11 and a pharmaceutically acceptable diluent.
14. The pharmaceutical composition of claim 13 , that is a sterile aqueous solution.
15. The pharmaceutical composition of claim 14 , comprising a buffer.
16. The pharmaceutical composition of claim 14 , wherein the diluent is saline or water.
17. A pharmaceutical composition comprising the dsRNA agent of claim 1 and a pharmaceutically acceptable diluent.
18. A pharmaceutical composition comprising the dsRNA agent of claim 8 and a pharmaceutically acceptable diluent.
19. A method of inhibiting expression of a SOD1 gene 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 the SOD1 gene, thereby inhibiting expression of the SOD1 gene in the cell.
20. A method of inhibiting expression of a SOD1 gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of claim 8 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the SOD1 gene, thereby inhibiting expression of the SOD1 gene in the cell.
21. A method of inhibiting expression of a SOD1 gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent of claim 11 ; and
(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of the SOD1 gene, thereby inhibiting expression of the SOD1 gene in the cell.
22. A method for treating a SOD1-associated neurodegenerative disease, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a dsRNA agent of claim 1 .
23. The method of claim 22 , wherein the SOD1-associated neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS).
24. The method of claim 23 , wherein the SOD1-associated neurodegenerative disease is inherited familial amyotrophic lateral sclerosis (fALS).
25. A method for treating a SOD1-associated neurodegenerative disease, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a dsRNA agent of claim 8 .
26. The method of claim 25 , wherein the SOD1-associated neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS).
27. The method of claim 26 , wherein the SOD1-associated neurodegenerative disease is inherited familial amyotrophic lateral sclerosis (fALS).
28. A method for treating a SOD1-associated neurodegenerative disease, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a dsRNA agent of claim 11 .
29. The method of claim 28 , wherein the SOD1-associated neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS).
30. The method of claim 29 , wherein the SOD1-associated neurodegenerative disease is inherited familial amyotrophic lateral sclerosis (fALS).