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 .- 102 . (canceled) 
     
     
         103 . A compound comprising:
 a modified oligonucleotide consisting of 15 to 19 linked nucleosides and complementary to a differentiating polymorphism site, wherein the nucleoside at position 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the differentiating polymorphism;   and wherein at least one of positions 2, 3, 6, 9, 10, 11, 13, or 14 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, comprises a high-affinity sugar modification.   
     
     
         104 . The compound of  claim 103 , wherein the nucleoside that aligns with the differentiating polymorphism comprises a high-affinity sugar modification. 
     
     
         105 . The compound of  claim 103 , wherein the nucleoside immediately adjacent to and at the 5′-side of the nucleoside that aligns with the differentiating polymorphism comprises a high-affinity sugar modification. 
     
     
         106 . The compound of  claim 103 , wherein the nucleoside immediately adjacent to and at the 3′-side of the nucleoside that aligns with the differentiating polymorphism comprises a high-affinity sugar modification. 
     
     
         107 . The compound of  claim 106 , wherein the modified oligonucleotide is 100% complementary to the single nucleotide polymorphism site. 
     
     
         108 . The compound of  claim 106 , wherein the high-affinity sugar modification is a bicyclic sugar. 
     
     
         109 . The compound of  claim 108 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         110 . The compound of  claim 108 , wherein the bicyclic sugar comprises a 4′-(CH 2 )—O-2′ bridge. 
     
     
         111 . The compound of  claim 106 , wherein the high-affinity sugar modification is a 2′-O-methoxyethyl nucleoside. 
     
     
         112 . The compound of  claim 106 , wherein at least one of positions 2, 3, 13, and 14 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, comprises a high-affinity sugar modification. 
     
     
         113 . The compound of  claim 106 , wherein each of nucleosides at positions 2, and 13 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, comprises a high-affinity sugar modification. 
     
     
         114 . The compound of  claim 112 , wherein the high-affinity sugar modification is a bicyclic sugar. 
     
     
         115 . The compound of  claim 114 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         116 . The compound of  claim 113 , wherein the high-affinity sugar modification is a bicyclic sugar. 
     
     
         117 . The compound of  claim 116 , wherein the bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         118 . The compound of  claim 106 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         119 . The compound of  claim 106 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         120 . The compound of  claim 113 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         121 . The compound of  claim 113 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage 
     
     
         122 . The compound of  claim 106 , comprising a pharmaceutically acceptable carrier or diluent.