Angiotensinogen (AGT) iRNA compositions and methods of use thereof
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsDonald Foster, Brian Bettencourt, Klaus Charisse, Gregory Hinkle, Satyanarayana Kuchimanchi, Martin Maier, Stuart Milstein
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Abstract
The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the angiotensinogen (AGT) gene, and methods of using such RNAi agents to inhibit expression of AGT and methods of treating subjects having an AGT-associated disorder, e.g., hypertension.
Claims44
A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of angiotensinogen (AGT) in a cell, wherein said double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 2081-2104 of the nucleotide sequence of SEQ ID NO:
- 1, wherein the antisense strand is substantially complementary to the sense strand, wherein each of the sense strand and the antisense strand is independently 15 to 30 nucleotides in length, and wherein the RNAi agent comprises at least one modified nucleotide.
A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of angiotensinogen (AGT),
- wherein said double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 2081-2104 of SEQ ID NO:1, and said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
- 2,
- wherein each of the sense strand and the antisense strand is independently 15 to 30 nucleotides in length,
- wherein substantially all of the nucleotides of said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
- wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
- wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
A double-stranded ribonucleic acid (RNAi) agent comprising a sense strand and an antisense strand, wherein said sense strand comprises the nucleotide sequence of 5′-UCUCCCACCUUUUCUUCUAAU-3′ (SEQ ID NO:499), and said antisense strand comprises the nucleotide sequence of 5′-AUUAGAAGAAAAGGUGGGAGACU-3′ (SEQ ID NO:537).
A composition comprising a modified antisense polynucleotide agent, wherein the agent comprises about 14 to about 30 contiguous nucleotides, wherein said agent is capable of inhibiting the expression of AGT in a cell, and comprises a nucleotide sequence substantially complementary to the nucleotide sequence of 5′-UCUCCCACCUUUUCUUCUAAU-3′ (SEQ ID NO:499).
A method of treating a subject having a hypertension, comprising subcutaneously administering to the subject a therapeutically effective amount of a double-stranded ribonucleic acid (RNAi) agent,
- wherein said double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region,
- wherein said sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 2081-2104 of SEQ ID NO:1, and said antisense strand comprises at least 15 nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
- 2,
- wherein each of the sense strand and the antisense strand is independently 15 to 30 nucleotides in length,
- wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoromodification,
- wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus,
- wherein substantially all of the nucleotides of said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
- wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and,
- wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus, thereby treating the subject.
Dependencies are inferred from the claim text.