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 about 4 to about 50 contiguous nucleotides, wherein at 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 ID NOs: 1-4. 
     
     
         2 . The single stranded antisense polynucleotide agent of  claim 1 , wherein the equivalent region is any one of the target regions of SEQ ID NO:1 provided in Table. 
     
     
         3 . (canceled) 
     
     
         4 . A single stranded antisense polynucleotide agent for inhibiting expression of angiotensinogen (AGT), wherein the agent comprises at least 8 contiguous nucleotides differing by no more than 3 nucleotides from any one of the nucleotide sequences listed in Table 3, and wherein the agent is about 8 to about 50 nucleotides in length. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The single stranded antisense polynucleotide agent of  claim 1 , wherein all of the nucleotides of the single stranded antisense polynucleotide agent comprise a nucleotide modification. 
     
     
         8 . The single stranded antisense polynucleotide 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 single stranded antisense polynucleotide agent of  claim 1 , wherein the nucleotide modifications comprise a modified sugar moiety selected from the group consisting of: a 2′-O-methoxyethyl modified sugar moiety modification, a 2′-methoxy modified sugar moiety modification, a 2′-O-alkyl modified sugar moiety modification, and a bicyclic sugar moiety modification. 
     
     
         16 . (canceled) 
     
     
         17 . The single stranded antisense polynucleotide agent of  claim 1 , wherein the nucleotide modifications comprise a 5-methylcytosine. 
     
     
         18 . The single stranded antisense polynucleotide agent of  claim 1 , wherein the nucleotide modifications comprise a modified internucleoside linkage. 
     
     
         19 . (canceled) 
     
     
         20 . The single stranded antisense polynucleotide 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 - 34 . (canceled) 
     
     
         35 . A single stranded antisense polynucleotide agent for inhibiting angiotensinogen (AGT) expression, comprising
 a gap segment consisting of linked deoxynucleotides;   a 5′-wing segment consisting of linked nucleotides;   a 3′-wing segment consisting of linked nucleotides;   wherein the gap segment is positioned between the 5′-wing segment and the 3′-wing segment and wherein each nucleotide of each wing segment comprises a modified sugar.   
     
     
         36 - 40 . (canceled) 
     
     
         41 . The single stranded antisense polynucleotide agent of  claim 1 , wherein the agent further comprises a ligand. 
     
     
         42 - 44 . (canceled) 
     
     
         45 . A pharmaceutical composition for inhibiting expression of an angiotensinogen (AGT) gene comprising the single stranded antisense polynucleotide 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 single stranded antisense polynucleotide agent of  claim 1 , thereby inhibiting expression of the AGT gene in the cell. 
     
     
         55 - 57 . (canceled) 
     
     
         58 . A method of treating a subject having a disease or disorder that would benefit from reduction in angiotensinogen (AGT) expression, the method comprising administering to the subject a therapeutically effective amount of the single stranded antisense polynucleotide agent of  claim 1 , thereby treating the subject. 
     
     
         59 - 73 . (canceled)