SNCA-TARGETING SIRNA COMPOSITIONS FOR TREATING SNCA-ASSOCIATED DISEASE
The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a SNCA gene, particularly in a CNS tissue, as well as methods of inhibiting expression of a SNCA gene and methods of treating subjects having a SNCA-associated neurodegenerative disease or disorder, e.g., Parkinson's Disease (PD), multiple system atrophy (MSA), Lewy body dementia (LBD), among other synucleinopathies, 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 4 modified or unmodified nucleotides from the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64,
wherein a, g, c and u are 2-O-methyl (2-OMe) A, G, C and U; Af, Gf, and Cf are 2-fluoro (2-F) A, G, and C; dA, dT, and dC are 2-deoxy A, T, and C; (Ahd) is 2′-O-hexadecyl adenosine-3′-phosphate; VP is Vinyl-phosphonate; and s is a phosphorothioate linkage.
2 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the sense strand differs by no more than 4 modified or unmodified nucleotides from the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
3 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand differs by no more than 3 modified or unmodified nucleotides from the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64.
4 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 3 , wherein the nucleotide sequence of the sense strand differs by no more than 3 modified or unmodified nucleotides from the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
5 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand differs by no more than 2 modified or unmodified nucleotides from the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64.
6 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 5 , wherein the nucleotide sequence of the sense strand differs by no more than 2 modified or unmodified nucleotides from the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
7 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the nucleotide sequence of the antisense strand differs by no more than 1 modified or unmodified nucleotides from the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64.
8 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein the nucleotide sequence of the sense strand differs by no more than 1 modified or unmodified nucleotides from the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
9 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the antisense strand comprises the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64.
10 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 9 , wherein the sense strand comprises the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
11 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein the antisense strand consists of the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64.
12 . The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 11 , the sense strand consists of the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21.
13 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a cell, comprising contacting the cell with the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 .
14 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a cell, comprising contacting the cell with the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 12 .
15 . A pharmaceutical composition for inhibiting expression of a gene encoding α-Synuclein (SNCA), comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient or carrier.
16 . A pharmaceutical composition for inhibiting expression of a gene encoding α-Synuclein (SNCA) comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 12 , and a pharmaceutically acceptable excipient or carrier.
17 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 15 .
18 . The method of claim 17 , wherein the subject has been diagnosed with Parkinson's disease.
19 . The method of claim 17 , wherein the pharmaceutical composition is administered intrathecally.
20 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 16 .
21 . The method of claim 20 , wherein the subject has been diagnosed with Parkinson's disease.
22 . The method of claim 20 , wherein the pharmaceutical composition is administered intrathecally.
23 . A sodium salt of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand consists of the nucleotide sequence 5′-gsasgca(Ahd)guGfAfCfaaauguugsgsa-3′ of SEQ ID NO:21 and the antisense strand consists of the nucleotide sequence 5′-VPusdCscadAcdAuuugdTcAfcuugcucsusu-3′ of SEQ ID NO:64, wherein a, g, c and u are 2-O-methyl (2-OMe) A, G, C and U; Af, Gf, and Cf are 2-fluoro (2-F) A, G, and C; dA, dT, and dC are 2-deoxy A, T, and C; (Ahd) is 2′-O-hexadecyl adenosine-3′-phosphate; VP is Vinyl-phosphonate; and s is a phosphorothioate linkage.
24 . A pharmaceutical composition for inhibiting expression of a gene encoding α-Synuclein (SNCA), comprising the sodium salt of a double stranded ribonucleic acid (dsRNA) agent of claim 23 and a pharmaceutically acceptable excipient or carrier.
25 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a cell, comprising contacting the cell with the sodium salt of a double stranded ribonucleic acid (dsRNA) agent of claim 23 .
26 . A method for inhibiting expression of a gene encoding α-Synuclein (SNCA) in a subject, comprising administering to the subject the pharmaceutical composition of claim 23 .
27 . The method of claim 26 , wherein the subject has been diagnosed with Parkinson's disease.
28 . The method of claim 26 , wherein the subject has been diagnosed with multiple system atrophy (MSA) or Lewy body dementia (LBD).
29 . The method of claim 26 , wherein the pharmaceutical composition is administered intrathecally.
30 . A method for treating an SNCA-associated disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , thereby treating an SNCA-associated disease in the subject.