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 for inhibiting expression of Huntingtin (HTT) in a cell, wherein the dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a region of complementarity to intron 1 retained in mutant HTT mRNA, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense nucleotide sequences in any one of Tables 2-3 and 5-6.
2 . The dsRNA agent of claim 1 , wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any one of the nucleotide sequence of nucleotides 5790-5810; 5791-5811; 5924-5944; 5925-5945; 5998-6018; 6063-6083; 6064-6084; 6194-6214; 6195-6215; 6211-6231, 5922-5944, 6059-6106 6059-6084 6068-6092 6076-6106 6191-6231 6191-6215 6191-6214; 6192-6215 6198-6231; or 6198-6224 of SEQ ID NO:11.
3 - 5 . (canceled)
6 . A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Huntingtin (HTT) in a cell, wherein the dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any one of the antisense strand nucleotide sequences of a duplex selected from the group consisting of AD-1718647; AD-1718648; AD-1718649; AD-1718653; AD-1718654 AD-1718655; AD-1718656; AD-1718660; AD-1718662; AD-1718663; AD-1718669; AD-1718670; AD-1718673; AD-1718674; AD-1718676; AD-1718677; AD-1718678; AD-1718679; AD-1718680; AD-1718682; AD-1718683; AD-1718702; AD-1718715; AD-1718717; or AD-1718721.
7 - 10 . (canceled)
11 . The dsRNA agent of claim 1 , wherein the sense strand, the antisense strand, or both the sense strand and the antisense strand is conjugated to one or more lipophilic moieties.
12 . The dsRNA agent of claim 11 , wherein the lipophilic moiety is conjugated to one or more internal positions in the double stranded region of the dsRNA agent.
13 - 25 . (canceled)
26 . The dsRNA agent of claim 11 , 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, and positions 6-10 and 15-18 on the antisense strand, counting from the 5′-end of each strand.
27 - 33 . (canceled)
34 . The dsRNA agent of claim 11 , wherein the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain.
35 - 39 . (canceled)
40 . The dsRNA agent of claim 1 , wherein the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage.
41 . The dsRNA agent of claim 1 , wherein at least one nucleotide of the dsRNA agent comprises a nucleotide modification.
42 . (canceled)
43 . The dsRNA agent of claim 41 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification.
44 . The dsRNA agent of claim 41 , wherein at least one of the nucleotide modifications is selected from the group a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy nucleotide modification, a 2′-5′-linked ribonucleotide (3′-RNA) modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino nucleotide modification, a 2′-O-allyl nucleotide modification, 2′-C-alkyl nucleotide modification, 2′-hydroxly nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a 5′-phosphorothioate group modification, a nucleotide comprising a 5′-methylphosphonate group modification, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic modification, a nucleotide comprising vinyl phosphonate modification, a nucleotide comprising adenosine-glycol nucleic acid (GNA) modification, a glycol nucleic acid S-Isomer (S-GNA) modification, a nucleotide comprising 2-hydroxymethyl-tetrahydrofurane-5-phosphate modification, a nucleotide comprising 2′-deoxythymidine-3′phosphate modification, a nucleotide comprising 2′-deoxyguanosine-3′-phosphate modification, and a terminal nucleotide linked to a cholesteryl derivative modification, a dodecanoic acid bisdecylamide group modification; an acytidine-2′-phosphate modification, a guanosine-2′-phosphate modification, a uridine-2′-phosphate modification, a adenosine-2′-phosphate modification, a 2′-O-hexadecyl-adenosine-3′-phosphate modification, a 2′-O-hexadecyl-cytidine-3′-phosphate modification, a 2′-O-hexadecyl-guanosine-3′-phosphate modification, and a 2′-O-hexadecyl-uridine-3′-phosphate modification, and combinations thereof.
45 - 72 . (canceled)
73 . The dsRNA agent of claim 1 , further comprising at least one phosphorothioate internucleotide linkage.
74 . (canceled)
75 . The dsRNA agent of claim 1 , wherein each strand is no more than 30 nucleotides in length.
76 . The dsRNA agent of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.
77 . (canceled)
78 . The dsRNA agent of claim 1 , wherein the double stranded region is 15-30 nucleotide pairs in length.
79 - 95 . (canceled)
96 . The dsRNA agent of claim 1 , further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.
97 - 99 . (canceled)
100 . A cell containing the dsRNA agent of claim 1 .
101 . A pharmaceutical composition for inhibiting expression of a gene encoding HTT, comprising the dsRNA agent of claim 1 .
102 . (canceled)
103 . A method of inhibiting expression of a huntingtin (HTT) 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 HTT gene, thereby inhibiting expression of the HTT gene in the cell.
104 - 108 . (canceled)
109 . 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 of claim 1 , thereby treating the subject.
110 - 117 . (canceled)