Huntingtin (HTT) iRNA agent compositions and methods of use thereof
The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a Huntingtin (HTT) gene, as well as methods of inhibiting expression of an HTT gene and methods of treating subjects having an HTT-associated disease or disorder, e.g., Huntington's disease, using such dsRNAi agents and compositions.
1. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, for inhibiting expression of Huntingtin (HTT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 (SEQ ID NO:65) and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; s is a phosphorothioate linkage; Af, Cf, and Gf are 2′-fluoro A, C, and G, respectively; (Chd) is 2′-O-hexadecyl-cytosine-3′-phosphate; C2p is cytidine-2′-phosphate; dA, dG, and dC are 2′-deoxy A, G, and C, respectively; and VP is 5′-vinyl phosphonate.
2. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
3. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 2 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
4. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 1 nucleotide from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
5. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
6. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand consists of the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
7. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 17 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 17 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
8. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 18 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 18 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
9. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the sense strand comprises at least 19 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises at least 19 contiguous nucleotides differing by no more than 4 nucleotides from the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79.
10. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1 - 9 .
11. A pharmaceutical composition for inhibiting expression of a gene encoding HTT, comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1 - 9 .
12. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in an unbuffered solution.
13. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a buffer solution.
14. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, for inhibiting expression of Huntingtin (HTT) in a cell, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand comprises the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; s is a phosphorothioate linkage; Af, Cf, and Gf are 2′-fluoro A, C, and G, respectively; (Chd) is 2′-O-hexadecyl-cytosine-3′-phosphate; C2p is cytidine-2′-phosphate; dA, dG and dC are 2′-deoxy A, G, and C, respectively; and VP is 5′-vinyl phosphonate.
15. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 14 .
16. A pharmaceutical composition for inhibiting expression of a gene encoding HTT, comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 15 .
17. The pharmaceutical composition of claim 16 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in an unbuffered solution.
18. The pharmaceutical composition of claim 17 , wherein the unbuffered solution is saline or water.
19. The pharmaceutical composition of claim 16 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a buffer solution.
20. The pharmaceutical composition of claim 19 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
21. The pharmaceutical composition of claim 19 , wherein the buffer solution is phosphate buffered saline (PBS).
22. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, for inhibiting expression of Huntingtin (HTT) in a cell,
wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand consists of the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; s is a phosphorothioate linkage; Af, Cf, and Gf are 2′-fluoro A, C, and G, respectively; (Chd) is 2′-O-hexadecyl-cytosine-3′-phosphate; C2p is cytidine-2′-phosphate; dA, dG and dC are 2′-deoxy A, G, and C, respectively; and VP is 5′-vinyl phosphonate.
23. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 22 .
24. A pharmaceutical composition for inhibiting expression of a gene encoding HTT, comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 22 .
25. The pharmaceutical composition of claim 24 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in an unbuffered solution.
26. The pharmaceutical composition of claim 25 , wherein the unbuffered solution is saline or water.
27. The pharmaceutical composition of claim 24 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a buffer solution.
28. The pharmaceutical composition of claim 27 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
29. The pharmaceutical composition of claim 27 , wherein the buffer solution is phosphate buffered saline (PBS).
30. A sodium salt of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Huntingtin (HTT) in a cell,
wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-gscsgac(Chd)CfuGfGfAfaaagcugasusa-3′ of SEQ ID NO:65 and the antisense strand consists of the nucleotide sequence 5′-VPusAfsucdAg(C2p)uuuudCcAfgdGgucgcscsg-3′ of SEQ ID NO:79,
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; s is a phosphorothioate linkage; Af, Cf, and Gf are 2′-fluoro A, C, and G, respectively; (Chd) is 2′-O-hexadecyl-cytosine-3′-phosphate; C2p is cytidine-2′-phosphate; dA, dG and dC are 2′-deoxy A, G, and C, respectively; and VP is 5′-vinyl phosphonate.