Methods and compositions for modulating alpha-1-antitrypsin expression

Abstract

Disclosed herein are methods for decreasing AlAT 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 AlAT 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 . A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 8, contiguous nucleobases complementary to an equal length portion of nucleobases 459 to 513, 1349 to 1597, 1561 to 1597, 1564 to 1583, or 1575 to 1594 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1. 
     
     
         2 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1. 
     
     
         11 - 23 . (canceled) 
     
     
         24 . A composition comprising the compound of  claim 1  or a salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         25 - 35 . (canceled) 
     
     
         36 . A method of reducing AlAT in an animal comprising administering to the animal a modified oligonucleotide targeting an AlAT nucleic acid sequence as shown in SEQ ID NO: 1. 
     
     
         37 . The method of  claim 36 , wherein the modified oligonucleotide targeting A1AT consists of 12 to 30 linked nucleosides and is at least 90% complementary to the AlAT nucleic acid. 
     
     
         38 . A method of treating, ameliorating and/or preventing an A1ATD associated liver disease in an animal at risk for the A1ATD associated liver disease comprising,
 (a) identifying the animal at risk for developing the A1ATD associated liver disease; and   (b) administering to the at risk animal a therapeutically effective amount of a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the modified oligonucleotide is at least 90% complementary to an AlAT nucleic acid,   thereby treating, ameliorating and/or preventing the A1ATD associated liver disease in the at risk animal.   
     
     
         39 - 49 . (canceled)