Compositions for modulating expression of c9orf72 antisense transcript

Abstract

Disclosed herein are compositions and methods for reducing expression of C9ORF72 antisense transcript in an animal with C9ORF72 antisense transcript specific inhibitors. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C9ORF72 antisense transcript specific inhibitors include antisense compounds.

1 . A compound comprising a C9ORF72 antisense transcript specific inhibitor, wherein the C9ORF72 antisense transcript specific inhibitor is a modified oligonucleotide consisting of 12-30 linked nucleosides, wherein at least one nucleoside of the antisense oligonucleotide comprises a hypoxanthine nucleobase, wherein the modified oligonucleotide has a nucleobase sequence that is at least 90% complementary to a C9ORF72 antisense transcript, and wherein the modified oligonucleotide comprises at least one modified internucleoside linkage and/or at least one modified nucleoside comprising a modified sugar. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein the modified oligonucleotide consists of 16-25 linked nucleosides. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to a C9ORF72 antisense transcript. 
     
     
         11 . The compound of  claim 1 , wherein the C9ORF72 antisense transcript has the nucleobase sequence of SEQ ID NO: 13. 
     
     
         12 . The compound of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of a sequence selected from SEQ ID NO: 30-96, 98, or 99. 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         15 . The compound of  claim 14 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         16 . The compound of  claim 14 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         17 . The compound of  claim 14  wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The compound of  claim 21 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group. 
     
     
         25 . The compound of  claim 1 , wherein the modified oligonucleotide is a gapmer. 
     
     
         26 - 92 . (canceled) 
     
     
         93 . The compound of  claim 1 , wherein the modified oligonucleotide is a single-stranded modified oligonucleotide. 
     
     
         94 - 145 . (canceled) 
     
     
         146 . A compound comprising a C9ORF72 antisense transcript specific inhibitor, wherein the C9ORF72 antisense transcript specific inhibitor is a modified oligonucleotide consisting of 12-30 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising at least 12 contiguous nucleobases that are complementary to a hexanucleotide repeat expansion in a C9ORF72 antisense transcript, and wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         147 . The compound of  claim 146 , wherein the modified oligonucleotide consists of 16-25 linked nucleosides. 
     
     
         148 . The compound of  claim 146 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 90% complementary to the C9ORF72 antisense transcript. 
     
     
         149 . The compound of  claim 146 , wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to the C9ORF72 antisense transcript. 
     
     
         150 . The compound of  claim 146 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 16 contiguous nucleobases of a sequence selected from SEQ ID NOs: 47-49, 85-96, 98, or 99. 
     
     
         151 . The compound of  claim 146 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         152 . The compound of  claim 151 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         153 . The compound of  claim 151 , wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         154 . The compound of  claim 151 , wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage. 
     
     
         155 . The compound of  claim 146 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group. 
     
     
         156 . The compound of  claim 146 , wherein the modified oligonucleotide is a gapmer. 
     
     
         157 . The compound of  claim 146 , wherein the modified oligonucleotide is a single-stranded modified oligonucleotide.