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.

1 . An antisense polynucleotide agent for inhibiting expression of angiotensinogen (AGT), wherein the agent comprises about 4 to about 50 contiguous nucleotides, wherein al least one of the contiguous nucleotides is a modified nucleotide, and wherein the nucleotide sequence of the agent is about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of SEQ NOs:1-4. 
     
     
         2 . The agent of  claim 1 , wherein the equivalent region is any one of the target regions of SEQ ID NO:1 provided in Table 3. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The agent of  claim 1 , wherein substantially all of the nucleotides of the antisense polynucleotide agent are modified nucleotides. 
     
     
         7 . (canceled) 
     
     
         8 . The agent of  claim 1 , which is 10 to 40 nucleotides in length; 10 to 30 nucleotides in length; 18 to 30 nucleotides in length: 10 to 24 nucleotides in length: 18 to 24 nucleotides in length: or 20 nucleotides in length. 
     
     
         9 .- 14 . (canceled) 
     
     
         15 . 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. 
     
     
         16 . (canceled) 
     
     
         17 . The agent of  claim 1 , wherein the modified nucleotide is a 5-methylcytosine. 
     
     
         18 . The agent of  claim 1 , wherein the modified nucleotide comprises a modified internucleoside linkage. 
     
     
         19 . (canceled) 
     
     
         20 . 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. 
     
     
         21 . The agent of  claim 20 , wherein the agent is a gapmer comprising a gap segment comprised of linked T-deoxynucleotides positioned between a 5′ and a 3′ wing segment. 
     
     
         22 . The agent of  claim 20 , 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. 
     
     
         23 . The agent of  claim 21 , wherein the 5′-wing segment and the 3′-wing segment are each independently 1 to 6 nucleotides in length. 
     
     
         24 . (canceled) 
     
     
         25 . The agent of  claim 21 , wherein the gap segment is 5 to 14 nucleotides in length. 
     
     
         26 .- 40 . (canceled) 
     
     
         41 . The agent of  claim 1 , wherein the agent further comprises a ligand. 
     
     
         42 . The agent of  claim 41 , wherein the antisense polynucleotide agent is conjugated to the ligand at the 3′-terminus. 
     
     
         43 . The agent of  claim 41 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         44 . The agent of  claim 41 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         45 . A pharmaceutical composition for inhibiting expression of an angiotensinogen (AGT) gene comprising the agent of  claim 1 . 
     
     
         46 .- 53 . (canceled) 
     
     
         54 . A method of inhibiting angiotensinogen (AGT) expression in a cell, the method comprising contacting the cell with the agent of  claim 1  or a pharmaceutical composition of  claim 45 , thereby inhibiting expression of the AGT gene in the cell. 
     
     
         55 . The method of  claim 54 , wherein the cell is within a subject. 
     
     
         56 .- 73 . (canceled)