Compositions and their uses directed to huntingtin

Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of huntingtin in a cell, tissue or animal. Further provided are methods of slowing or preventing Huntington's disease progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntingtin's disease in an individual susceptible to Huntingtin's Disease. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.

1 . A compound comprising a modified oligonucleotide consisting of 12 to 35 linked nucleosides, wherein at least 12 consecutive nucleobases of said modified oligonucleotide are at least 90% complementary to a region of human huntingtin that encodes a plurality of CAG repeats. 
     
     
         2 . The compound of  claim 1 , wherein said modified oligonucleotide is 100% complementary to the region of human huntingtin that encodes the plurality of CAG repeats. 
     
     
         3 . The compound of  claim 1 , consisting of a single-stranded modified oligonucleotide. 
     
     
         4 . The compound of  claim 1 , wherein said modified oligonucleotide is at least at least 95% complementary to SEQ ID NO: 4. 
     
     
         5 . The compound of  claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 4. 
     
     
         6 . The compound of  claim 1 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage. 
     
     
         7 . The compound of  claim 6 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         8 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         9 . The compound of  claim 8 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         10 . The compound of  claim 8 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl moiety. 
     
     
         11 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         12 . The compound of  claim 11 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         13 . The compound of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   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.   
     
     
         14 . The compound of  claim 13 , 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-methoxyethyl sugar; and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.   
     
     
         15 . The compound of  claim 14 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         16 . The compound of  claim 1 , wherein said modified oligonucleotide consists of 17 to 25 linked nucleosides. 
     
     
         17 . The compound of  claim 1 , wherein said modified oligonucleotide consists of 19 to 23 linked nucleosides. 
     
     
         18 . The compound of  claim 1 , wherein said modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         19 . The compound of  claim 1 , wherein said modified oligonucleotide comprises a nucleobase sequence selected from the group consisting of SEQ ID NO: 48, 49, 50, 51, 52, and 53. 
     
     
         20 . The compound of  claim 1 , wherein said modified oligonucleotide comprises ISIS 388829, ISIS 388830, ISIS 388831, ISIS 388832, ISIS 388833, or ISIS 388834. 
     
     
         21 . The compound of  claim 1 , wherein said modified oligonucleotide consists of a nucleobase sequence selected from the group consisting of SEQ ID NO: 48, 49, 50, 51, 52, and 53. 
     
     
         22 . The compound of  claim 1 , wherein said modified oligonucleotide consists of ISIS 388829, ISIS 388830, ISIS 388831, ISIS 388832, ISIS 388833, or ISIS 388834. 
     
     
         23 . The compound of  claim 1 , wherein the 5′ nucleotide of the modified oligonucleotide is T. 
     
     
         24 . The compound of  claim 1 , wherein the 5′ nucleotide of the modified oligonucleotide is C. 
     
     
         25 . A composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.