Polynucleotide agents targeting angiotensinogen (agt) and methods of use thereof

Abstract

The invention relates to polynucleotide agents, e.g., antisense polynucleotide agents, targeting an angiotensinogen (AGT) gene, and methods of using such polynucleotide agents to inhibit expression of AGT and to treat subjects having an AGT-associated disease, e.g., hypertension.

We claim: 
     
         1 . A single stranded antisense polynucleotide agent for inhibiting expression of angiotensinogen (AGT), wherein the agent comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-AACAAGCTGGTCGGTUGGAA-3′ (SEQ ID NO:215),
 wherein at least one of the contiguous nucleotides is a modified nucleotide, and 
 wherein the agent is about 15 to about 30 nucleotides in length. 
 
     
     
         2 . The agent of  claim 1 , which is 18 to 24 nucleotides in length. 
     
     
         3 . The agent of  claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         4 . The agent of  claim 1 , wherein all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         5 . The agent of  claim 1 , wherein the modified nucleotide comprises a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 
     
     
         6 . The agent of  claim 5 , wherein the bicyclic sugar moiety has a (—CH2-)n group forming a bridge between the 2′ oxygen and the 4′ carbon atoms of the sugar ring, wherein n is 1 or 2. 
     
     
         7 . The agent of  claim 1 , wherein the modified nucleotide is a 5-methylcytosine. 
     
     
         8 . The agent of  claim 1 , wherein the modified nucleotide comprises a modified internucleoside linkage. 
     
     
         9 . The agent of  claim 8 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         10 . The agent of  claim 1 , comprising a plurality of 2′-deoxynucleotides flanked on each side by at least one nucleotide having a modified sugar moiety. 
     
     
         11 . The agent of  claim 10 , wherein the agent is a gapmer comprising a gap segment comprised of linked 2′-deoxynucleotides positioned between a 5′ and a 3′ wing segment. 
     
     
         12 . The agent of  claim 10 , wherein the modified sugar moiety is selected from the group consisting of a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 
     
     
         13 . The agent of  claim 11 , wherein the 5′-wing segment is 1 to 6 nucleotides in length. 
     
     
         14 . The agent of  claim 11 , wherein the 3′-wing segment is 1 to 6 nucleotides in length. 
     
     
         15 . The agent of  claim 11 , wherein the gap segment is 5 to 14 nucleotides in length. 
     
     
         16 . The agent of  claim 1 , wherein the agent further comprises a ligand. 
     
     
         17 . The agent of  claim 16 , wherein the agent is conjugated to the ligand at the 3′-terminus. 
     
     
         18 . The agent of  claim 16 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         19 . A pharmaceutical composition for inhibiting expression of an angiotensinogen (AGT) gene comprising the agent of  claim 1 .