Selective reduction of allelic variants

Abstract

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

1 .- 97 . (canceled) 
     
     
         98 . A method of selectively reducing the expression of a mutant huntingtin allele in a cell, tissue, or animal comprising administering to the cell, tissue, or animal a compound comprising a modified, single-stranded antisense oligonucleotide complementary to the mutant huntingtin allele at a position comprising a single nucleotide polymorphism, wherein the expression of the mutant huntingtin allele is selectively reduced, and wherein the single nucleotide polymorphism is of rs6446723, rs3856973, rs2285086, rs363092, rs916171, rs6844859, rs7691627, rs4690073, rs11731237, rs362296, rs10015979, rs7659144, rs363096, rs362273, rs16843804, rs362271, rs362275, rs3121419, rs362272, rs3775061, rs34315806, rs363099, rs2298967, rs363064, rs363102, rs2798235, rs363080, rs363072, rs363125, rs362303, rs362310, rs10488840, rs362325, rs35892913, rs1936032, rs2276881, rs363070, rs12502045, rs3733217, rs2857936, rs12506200, rs762855, rs363081, rs363075, rs3025849, rs6855981, rs363144, rs3025838, rs362322, rs362307, and rs1006798. 
     
     
         99 . The method of  claim 98 , wherein the modified oligonucleotide consists of 15 to 20 linked nucleosides and position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism. 
     
     
         100 . The method of  claim 99 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         101 . The method of  claim 98 , wherein the modified oligonucleotide consists of 15 to 20 linked nucleosides and position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of the modified oligonucleotide, as counted from the 5′ terminus of the modified oligonucleotide, aligns with the single nucleotide polymorphism. 
     
     
         102 . The method of  claim 99 , wherein at least one nucleoside comprises a modified sugar. 
     
     
         103 . The method of  claim 100 , wherein the modified sugar is a high-affinity sugar modification. 
     
     
         104 . The method of  claim 101 , wherein the high-affinity sugar is a bicyclic sugar. 
     
     
         105 . The method of  claim 102 , wherein each bicyclic sugar comprises a 4′-CH(CH 3 )—O-2′ bridge. 
     
     
         106 . The method of  claim 101 , wherein the at least one modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         107 . The method of  claim 99 , wherein the modified oligonucleotide comprises a wing-gap-wing motif. 
     
     
         108 . The method of  claim 105 , wherein the wing-gap-wing motif is any of the group consisting of 2-9-6, 3-9-3, 3-9-4, 3-9-5, 4-7-4, 4-9-4, 4-9-5, 4-10-5, 4-11-4, 4-11-5, 5-7-5, 5-8-6, 5-9-3, 5-9-5, 5-10-4, 5-10-5, 6-7-6, 6-8-5, and 6-9-2. 
     
     
         109 . The method of  claim 106 , wherein each nucleoside positioned in the wing segment of the modified oligonucleotide comprises a 2′-O-methoxyethyl modification. 
     
     
         110 . The method of  claim 106 , wherein at least one of the wing regions comprises a 4′ to 2′ bicyclic nucleoside and at least one of the remaining wing nucleosides is a non-bicyclic 2′-modified nucleoside. 
     
     
         111 . The method of  claim 108 , wherein the non-bicyclic 2′-modified nucleoside is a 2′-O-methoxyethyl nucleoside. 
     
     
         112 . The method of  claim 108 , wherein the 4′ to 2′ bicyclic nucleoside is a 4′-CH(CH 3 )—O-2′ bicyclic nucleoside. 
     
     
         113 . The method of  claim 105 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         114 . The method of  claim 111 , wherein the at least one modified nucleobase is a 5′-methylcytosine. 
     
     
         115 . The method of  claim 99 , wherein the modified oligonucleotide is 95% complementary to the mutant huntingtin allele. 
     
     
         116 . The method of  claim 99 , wherein the modified oligonucleotide is 100% complementary to the mutant huntingtin allele. 
     
     
         117 . The method of  claim 106 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         118 . The method of  claim 115 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         119 . A method of treating, ameliorating, or slowing the onset or progression of Huntington's Disease, comprising administering to an animal a compound comprising a modified, single-stranded antisense oligonucleotide complementary to a mutant huntingtin allele at a position on the allele comprising a single nucleotide polymorphism site, wherein the compound administered to the animal treats, ameliorates or slows the onset or progression Huntington's Disease by selectively reducing the mutant huntingtin allele, and wherein the single nucleotide polymorphism site is rs6446723, rs3856973, rs2285086, rs363092, rs916171, rs6844859, rs7691627, rs4690073, rs11731237, rs362296, rs10015979, rs7659144, rs363096, rs362273, rs16843804, rs362271, rs362275, rs3121419, rs362272, rs3775061, rs34315806, rs363099, rs2298967, rs363064, rs363102, rs2798235, rs363080, rs363072, rs363125, rs362303, rs362310, rs10488840, rs362325, rs35892913, rs1936032, rs2276881, rs363070, rs12502045, rs3733217, rs2857936, rs12506200, rs762855, rs363081, rs363075, rs3025849, rs6855981, rs363144, rs3025838, rs362322, rs362307, and rs1006798.