Methods and compositions for modulating alpha-1-antitrypsin expression

Abstract

Disclosed herein are methods for decreasing A1AT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of fibrosis. Disclosed herein are methods for decreasing A1AT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of liver disease, such as, A1ATD associated liver disease, and pulmonary disease, such as, A1ATD associated pulmonary disease in an individual in need thereof. Methods for inhibiting A1AT mRNA and protein expression can also be used as a prophylactic treatment to prevent individuals at risk for developing a liver disease, such as, A1ATD associated liver disease and pulmonary disease, such as, A1ATD associated pulmonary disease.

1 - 3 . (canceled) 
     
     
         4 . A compound comprising a modified oligonucleotide consisting of 20 to 30 linked nucleosides and having a nucleobase sequence comprising a portion of at least 20 contiguous nucleobases that is 100% complementary to an equal length portion of nucleobases 1349 to 1597 of SEQ ID NO: 1, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1, and wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar. 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The compound of  claim 4 , wherein the modified oligonucleotide consists of 20 or 22 linked nucleosides. 
     
     
         10 . The compound of  claim 4 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         11 . The compound of  claim 4 , wherein the modified oligonucleotide is single-stranded. 
     
     
         12 . The compound of  claim 4 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         13 . The compound of  claim 12 , wherein at least one modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         14 . The compound of  claim 13 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         15 . The compound of  claim 4 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         16 . The compound of  claim 15 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 4 , wherein the modified sugar is a 2′-O-methoxyethyl. 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 4 , wherein the modified sugar is a bicyclic sugar. 
     
     
         21 . The compound of  claim 20 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         22 . The compound of  claim 4 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxy nucleosides;   a 5′ wing segment consisting of linked nucleosides;   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         23 . The compound of  claim 22 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides;   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyehtyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5′-methylcytosine.   
     
     
         24 . A composition comprising a compound according to  claim 4  or  claim 50  and a pharmaceutically acceptable carrier or diluent. 
     
     
         25 - 35 . (canceled) 
     
     
         36 . A method comprising administering to an animal the composition of  claim 24 . 
     
     
         37 - 43 . (canceled) 
     
     
         44 . The method of  claim 36 , wherein accumulation of A1AT aggregates is forestalled, prevented or delayed. 
     
     
         45 - 48 . (canceled) 
     
     
         49 . The method of  claim 36 , wherein administration of the modified oligonucleotide decreases TIMP1, collagen type 1, collagen type IV, collagen type III, MMP13, SMA, ALT and/or AST expression. 
     
     
         50 . The compound of  claim 4 , wherein the compound is a sodium salt.