Human chromosome 9 open reading frame 72 (C9ORF72) iRNA agent compositions and methods of use thereof
The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a human chromosome 9 open reading frame 72 (C9orf72) gene, as well as methods of inhibiting expression of a C9orf72 gene and methods of treating subjects having a C9orf72-associated disease or disorder, e.g., C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia or Huntington-Like Syndrome Due To C9orf72 Expansions, using such dsRNAi agents and compositions.
1 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of C9orf72, 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 sense strand and the antisense strand are each independently 17-25 nucleotides in length,
wherein the antisense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5′-AUUAAUCUUUAUCAGGUCUUUUC-3′ of SEQ ID NO:3,
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand independently comprise a nucleotide modification selected from the group consisting of a 2′-O-methyl nucleotide modification and a 2′-fluoro nucleotide modification,
wherein the dsRNA agent, or a salt thereof, comprises 6-8 phosphorothioate internucleotide linkages; and
wherein a lipophilic moiety containing a saturated or unsaturated C6-C18 hydrocarbon chain is conjugated to one or more 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.
2 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety is conjugated via a linker or carrier.
3 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 19-25 nucleotides in length.
4 . The dsRNA agent, or a salt thereof, of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
5 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the double stranded region is 17-25 nucleotide pairs in length.
6 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain.
7 . The dsRNA agent, or a salt thereof, of claim 6 , wherein the saturated or unsaturated C16 hydrocarbon chain is conjugated to position 6, counting from the 5′-end of the strand.
8 . 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.
9 . An isolated cell containing the dsRNA agent, or a salt thereof, of claim 1 .
10 . A pharmaceutical composition for inhibiting expression of a C9orf72, comprising the dsRNA agent, or a salt thereof, of claim 1 .
11 . A kit comprising the dsRNA agent, or a salt thereof, of claim 1 .
12 . A vial comprising the dsRNA agent, or a salt thereof, of claim 1 .
13 . A syringe comprising the dsRNA agent, or a salt thereof, of claim 1 .
14 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 18 contiguous nucleotides from the nucleotide sequence 5′-AUUAAUCUUUAUCAGGUCUUUUC-3′ of SEQ ID NO: 3.
15 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the antisense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-AUUAAUCUUUAUCAGGUCUUUUC-3′ of SEQ ID NO: 3.
16 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises at least 17 contiguous nucleotides from the nucleotide sequence 5′-AAAGACCUGAUAAAGAUUAAU-3′ of SEQ ID NO: 2.
17 . The dsRNA agent of claim 1 , which is in salt form.
18 . The dsRNA agent of claim 1 , which is in sodium salt form.
19 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 19-23 nucleotides in length.
20 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently 21-23 nucleotides in length.
21 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the one or more lipophilic moieties moiety is conjugated to the dsRNA agent, or a salt thereof, via a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction, or carbamate.
22 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.
23 . The dsRNA agent, or a salt thereof, of claim 2 , wherein the carrier is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl; or is an acyclic moiety based on a serinol backbone or a diethanolamine backbone.
24 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the 3′ end of the sense strand is protected via an end cap which is a cyclic group having an amine, said cyclic group being selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl, and decalinyl.
25 . The dsRNA agent, or a salt thereof, of claim 8 , wherein the phosphate mimic is a 5′-vinyl phosphonate (VP).