Selective reduction of allelic variants

Abstract

Disclosed herein are antisense compounds and methods for selectively reducing expression of an allelic variant of a gene containing a single nucleotide polymorphism (SNP). Such methods, compounds, and composition are useful to treat, prevent, or ameliorate diseases, including neurodegenerative diseases, such as Huntington's Disease (HD).

1 . A single-stranded modified oligonucleotide consisting of 19 to 22 linked nucleosides and complementary to a single nucleotide polymorphism site, wherein the nucleoside at position 11 or 12 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism rs362307 or rs362331;
 wherein the modified oligonucleotide comprises a wing-gap-wing motif, wherein the 5′ wing region is 4-6 nucleosides in length, the gap is 9-11 nucleosides in length, and the 3′ wing is 4-6 nucleosides in length, and wherein each nucleoside in the 5′ wing and each nucleoside in the 3′ wing is selected from a 2′-O-methyl nucleoside and a 2′-O-methoxyethyl nucleoside, and wherein each nucleoside in the gap is a 2′-deoxyribonucleoside; and 
 wherein the modified oligonucleotide comprises the nucleobase sequence 5′-GGCACAAGGGCACAGACTT-3′ (SEQ ID NO: 146), wherein each T may be a T or a U, or comprises the nucleobase sequence 5′-GTGCACACAGTAGATGAGG-3′ (SEQ ID NO: 218), wherein each T may be a T or a U. 
 
     
     
         2 . A single-stranded modified oligonucleotide consisting of 19 to 22 linked nucleosides and complementary to a single nucleotide polymorphism site, wherein the nucleoside at position 11 or 12 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism rs362307 or rs362331;
 wherein the modified oligonucleotide comprises a wing-gap-wing motif, wherein the 5′ wing region is 4-6 nucleosides in length, the gap is 9-11 nucleosides in length, and the 3′ wing is 4-6 nucleosides in length, and wherein each nucleoside in the 5′ wing and each nucleoside in the 3′ wing is selected from a 2′-O-methyl nucleoside and a 2′-O-methoxyethyl nucleoside, and wherein each nucleoside in the gap is a 2′-deoxyribonucleoside; and 
 wherein the modified oligonucleotide comprises a nucleobase sequence 100% complementary to nucleobases 181491-181509 of SEQ ID NO: 1 or nucleobases 155481-155499 of SEQ ID NO: 1. 
 
     
     
         3 . The modified oligonucleotide of  claim 1 , wherein at least one nucleoside in the 5′ wing or the 3′ wing is a 2′-O-methoxyethyl nucleoside. 
     
     
         4 . The modified oligonucleotide of  claim 1 , wherein each nucleoside in the 5′ wing and the 3′ wing is a 2′-O-methoxyethyl nucleoside. 
     
     
         5 . The modified oligonucleotide of  claim 2 , wherein at least one nucleoside in the 5′ wing or the 3′ wing is a 2′-O-methoxyethyl nucleoside. 
     
     
         6 . The modified oligonucleotide of  claim 2 , wherein each nucleoside in the 5′ wing and the 3′ wing is a 2′-O-methoxyethyl nucleoside. 
     
     
         7 . The modified oligonucleotide of  claim 1 , wherein at least one nucleoside in the 5′ wing or the 3′ wing is a 2′-O-methyl nucleoside. 
     
     
         8 . The modified oligonucleotide of  claim 1 , wherein each nucleoside in the 5′ wing and the 3′ wing is a 2′-O-methyl nucleoside. 
     
     
         9 . The modified oligonucleotide of  claim 2 , wherein at least one nucleoside in the 5′ wing or the 3′ wing is a 2′-O-methyl nucleoside. 
     
     
         10 . The modified oligonucleotide of  claim 2 , wherein each nucleoside in the 5′ wing and the 3′ wing is a 2′-O-methyl nucleoside. 
     
     
         11 . The compound of  claim 1 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         12 . The compound of  claim 2 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         13 . The compound of  claim 4 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         14 . The compound of  claim 6 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         15 . The compound of  claim 8 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         16 . The compound of  claim 10 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         17 . The compound of  claim 1 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         18 . The compound of  claim 2 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         19 . The compound of  claim 4 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         20 . The compound of  claim 6 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         21 . The compound of  claim 8 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         22 . The compound of  claim 10 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         23 . The compound of  claim 11 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         24 . The compound of  claim 12 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         25 . The compound of  claim 13 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         26 . The compound of  claim 14 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         27 . The compound of  claim 15 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         28 . The compound of  claim 16 , wherein at least one internucleoside linkage is a phosphodiester internucleoside linkage.