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, e.g., exon 1 of an 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 for inhibiting expression of Huntingtin (HTT), or a salt thereof,
wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-UAUCAGCUUUUCCAGGGUCGCCG-3′ of SEQ ID NO: 4200,
wherein all of the nucleotide of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification, and
wherein one or more lipophilic moieties are conjugated to one or more internal positions on the sense strand.
2 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, counting from the 5′-end of the strand.
3 . The dsRNA agent, or a salt thereof, of claim 2 , wherein the one or more lipophilic moieties are conjugated to one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15, and 17 on the sense strand, counting from the 5′-end of the strand.
4 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety is an aliphatic, alicyclic, or polyalicyclic compound.
5 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain.
6 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the nucleotide modifications are selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a thermally destabilizing modification,
when the thermally destabilizing modification is present, only the antisense strand of the dsRNA agent contains a thermally destabilizing modification.
7 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising at least one phosphorothioate internucleotide linkage.
8 . The dsRNA agent, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
9 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the double stranded region is 15-30 nucleotide pairs in length.
10 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 19-30 nucleotides in length.
11 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.
12 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides from the nucleotide sequence 5′-GCGACCCUGGAAAAGCUGAUA-3′ of SEQ ID NO: 3814.
13 . The dsRNA agent, or a salt thereof, of claim 7 , wherein the dsRNA agent, or a salt thereof, comprises 6-8 phosphorothioate internucleotide linkages.
14 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 19-23 nucleotides in length.
15 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 21-23 nucleotides in length.
16 . The dsRNA agent, or a salt thereof, of claim 12 , wherein only one lipophilic moiety is conjugated to one internal position on the sense strand.
17 . The dsRNA agent, or a salt thereof, of claim 16 , wherein the lipophilic moiety is conjugated to one of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strand, counting from the 5′-end of the strand.
18 . The dsRNA agent, or a salt thereof, of claim 17 , wherein the lipophilic moiety is a saturated C16 hydrocarbon chain.
19 . The dsRNA agent, or a salt thereof, of claim 16 , wherein the nucleotide modifications are selected from the group consisting of a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, and a thermally destabilizing modification,
when the thermally destabilizing modification is present, only the antisense strand of the dsRNA agent contains a thermally destabilizing modification.
20 . The dsRNA agent, or a salt thereof, of claim 16 , further comprising 6-8 phosphorothioate internucleotide linkages.
21 . The dsRNA agent, or a salt thereof, of claim 16 , wherein the antisense strand comprises a 3′ overhang of 2 nucleotides.
22 . The dsRNA agent, or a salt thereof, of claim 16 , wherein the double stranded region is 17-23 nucleotide pairs in length and each strand is independently 17-23 nucleotides in length.
23 . The dsRNA agent, or a salt thereof, of claim 16 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.
24 . An isolated cell containing the dsRNA agent, or a salt thereof, of claim 1 .
25 . A pharmaceutical composition for inhibiting expression of a gene encoding HTT, comprising the dsRNA agent, or a salt thereof, of claim 1 .
26 . A method of inhibiting expression of a huntingtin (HTT) gene in a cell, the method comprising:
(a) contacting the cell with the dsRNA agent, or a salt thereof, 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 HTT gene, thereby inhibiting expression of the HTT gene in the cell.
27 . A method of treating a subject diagnosed with an HTT-associated disease, the method comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of claim 1 , thereby treating the subject.
28 . The method of claim 27 , wherein the HTT-associated disease is Huntington's disease.
29 . The method of claim 27 , wherein the dsRNA agent, or a salt thereof, is administered to the subject intrathecally.