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).

What is claimed is: 
     
         1 .- 97 . (canceled) 
     
     
         98 . A method for determining whether an agent selectively inhibits expression of a first allelic variant of a gene relative to a second allelic variant of said gene wherein said first allelic variant comprises a first nucleotide at a SNP position and said second allelic variant comprises a second nucleotide at said SNP position, comprising:
 contacting a first cell, tissue or animal with said agent at one or more concentrations, wherein said first cell, tissue or animal is homozygous for said first nucleotide at said SNP position;   contacting a second cell, tissue or animal with said agent at one or more concentrations, wherein said second cell, tissue or animal is homozygous for said second nucleotide at said SNP position or is heterozygous for said first and said second nucleotides at said SNP position;   measuring inhibition of expression of said allelic variant in each of said cell, tissue or animal for each of said one or more concentrations of said agent; and   comparing said inhibition of expression in each of said cell, tissue or animal for each of said one or more concentrations of said agent to determine whether said agent selectively inhibits expression of said first allelic variant of said gene relative to said second allelic variant of said gene.   
     
     
         99 . The method of  claim 98 , further comprising the step of contacting a third cell, tissue, or animal with said agent at one or more concentrations, wherein said third cell, tissue, or animal is homozygous for said second nucleotide at said SNP position or is heterozygous for said first and said second nucleotides at said SNP position and has a different genotype than said first cell, tissue, or animal and said second cell, tissue, or animal. 
     
     
         100 . The method of  claim 98 , wherein said first allelic variant is a mutant allele and said second allelic variant is a wild-type allele. 
     
     
         101 . The method of  claim 98 , wherein said first allelic variant is a wild-type allele and said second allelic variant is a mutant allele. 
     
     
         102 . The method of  claim 101 , wherein said mutant allelic variant is associated with disease. 
     
     
         103 . The method of  claim 102 , wherein said disease is Huntington's Disease. 
     
     
         104 . The method of  claim 98 , wherein said first nucleotide is in linkage disequilibrium with a disease associated mutation. 
     
     
         105 . The method of  claim 98 , wherein said second nucleotide is in linkage disequilibrium with a disease associated mutation. 
     
     
         106 . The method of  claim 105 , wherein said disease associated mutation is a tri-nucleotide repeat expansion. 
     
     
         107 . The method of  claim 106 , wherein said tri-nucleotide repeat expansion is a CAG expansion. 
     
     
         108 . The method of  claim 107 , wherein said CAG expansion is in a HTT gene. 
     
     
         109 . The method of  claim 98 , wherein said first nucleotide is A. 
     
     
         110 . The method of  claim 109 , wherein said second nucleotide is any of C, G, or T. 
     
     
         111 . The method of  claim 109 , wherein said second nucleotide is any of A, G, or T. 
     
     
         112 . The method of  claim 98 , wherein said agent is an antisense compound. 
     
     
         113 . The method of  claim 112 , said antisense compound is an antisense oligonucleotide. 
     
     
         114 . The method of  claim 113 , wherein said antisense oligonucleotide is a gapmer. 
     
     
         115 . The method of  claim 113 , wherein said gapmer has a wing-gap-wing motif. 
     
     
         116 . The method of  claim 115 , wherein the wing-gap-wing motif is any one of the group consisting of 5-10-5, 2-9-6, 3-9-3, 3-9-4, 3-9-5, 4-7-4, 4-9-3, 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. 
     
     
         117 . The method of  claim 98 , wherein said SNP position is any of the group consisting of rs6446723, rs3856973, rs2285086, rs363092, rs916171, rs6844859, rs7691627, rs4690073, rs2024115, rs11731237, rs362296, rs10015979, rs7659144, rs363096, rs362273, rs16843804, rs362271, rs362275, rs3121419, rs362272, rs3775061, rs34315806, rs363099, rs2298967, rs363088, rs363064, rs363102, rs2798235, rs363080, rs363072, rs363125, rs362303, rs362310, rs10488840, rs362325, rs35892913, rs363102, rs363096, rs11731237, rs10015979, rs363080, rs2798235, rs1936032, rs2276881, rs363070, rs35892913, rs12502045, rs6446723, rs7685686, rs3733217, rs6844859, rs362331, rs1143646, rs2285086, rs2298969, rs4690072, rs916171, rs3025849, rs7691627, rs4690073, rs3856973, rs363092, rs362310, rs362325, rs363144, rs362303, rs34315806, rs363099, rs363081, rs3775061, rs2024115, rs10488840, rs363125, rs362296, rs2298967, rs363088, rs363064, rs362275, rs3121419, rs3025849, rs363070, rs362273, rs362272, rs362306, rs362271, rs363072, rs16843804, rs7659144, rs363120, and rs12502045.