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AssigneeAlnylam Pharmaceuticals, Inc.
InventorsJEFFREY ZUBER, JAMES D. MCININCH, MARK K. SCHLEGEL, ADAM CASTORENO
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Carbonic anhydrase inhibitors have been shown to reduce aqueous humor production and thereby reduce intraocular pressure in the eye. Accordingly, there is a need for agents that can selectively and efficiently inhibit expression of the CA2 gene such that subjects having a CA2-associated disorder, such as glaucoma, can be effectively treated. The disclosure relates to double-stranded ribonucleic acid (dsRNA) compositions targeting carbonic anhydrase 2 (CA2), and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of carbonic anhydrase 2.
A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of Carbonic anhydrase 2 (CA2), wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, from one of the antisense sequences listed in any one of Tables 3-10, and wherein the sense strand comprises a nucleotide sequence comprising at least 15 contiguous nucleotides, with 0, 1, 2, or 3 mismatches, from a sense sequence listed in any one of Tables 3-10 that corresponds to the antisense sequence and wherein the dsRNA agent comprises at least one modified nucleotide.
The dsRNA agent of any of the preceding claims, wherein no more than five of the sense strand nucleotides and not more than five of the nucleotides of the antisense strand are unmodified nucleotides.
The dsRNA agent of any of the preceding claims, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification.
The dsRNA agent of any of the preceding claims, wherein at least one of the modified nucleotides is selected from the group consisting of a deoxy-nucleotide, a 3′-terminal deoxythimidine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, a nucleotide comprising a 5′-phosphate mimic, a glycol modified nucleotide, and a 2-O—(N-methylacetamide) modified nucleotide;
The dsRNA agent of any of the preceding claims, wherein at least one strand comprises a 3′ overhang of at least 2 nucleotides.
The dsRNA agent of any of the preceding claims, wherein the double stranded region is 15-30 nucleotide pairs in length.
The dsRNA agent of any of the preceding claims, wherein each strand has 19-30 nucleotides.
The dsRNA agent of any of the preceding claims, wherein the agent comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
The dsRNA agent of any one of the preceding claims, further comprising a phosphate or phosphate mimic at the 5′-end of the antisense strand.
A dsRNA agent that targets a hotspot region of a Carbonic anhydrase 2 (CA2) mRNA.
Dependencies are inferred from the claim text.