Compositions and methods for modulation of smn2 splicing

Abstract

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a cell, tissue or animal. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy.

1 . An antisense oligonucleotide targeted to intron 6, exon 7 or intron 7 of a nucleic acid molecule encoding SMN2, wherein said oligonucleotide is 12 to 20 nucleotides in length and comprises a 2′-O-methoxyethyl sugar modification at each position. 
     
     
         2 . The oligonucleotide of  claim 1  which is 12 nucleotides in length. 
     
     
         3 . The oligonucleotide of  claim 1  which is 15 nucleotides in length. 
     
     
         4 . The oligonucleotide of  claim 1  which is 18 nucleotides in length. 
     
     
         5 . The oligonucleotide of  claim 1  which is targeted to an intronic splicing silencer element. 
     
     
         6 . The oligonucleotide of  claim 1  which is targeted to an exonic splicing silencer element. 
     
     
         7 . The oligonucleotide of  claim 1  which is targeted to intron 6. 
     
     
         8 . The oligonucleotide of  claim 7 , wherein the target site of said oligonucleotide is nucleotide 5, 6, 7 or 8 of SEQ ID NO: 1. 
     
     
         9 . The oligonucleotide of  claim 7 , wherein the nucleotide sequence of said oligonucleotide comprises at least an 8-nucleobase portion of SEQ ID NO: 6, 7, 8, 9, 10, 11, 12 or 13. 
     
     
         10 . The oligonucleotide of  claim 1  which is targeted to exon 7. 
     
     
         11 . The oligonucleotide of  claim 10  wherein the target site of said oligonucleotide is nucleotide 64, 65, 66, 67, 68, 94, 95, 96 or 97 of SEQ ID NO: 1. 
     
     
         12 . The oligonucleotide of  claim 10 , wherein the nucleotide sequence of said oligonucleotide comprises at least an 8-nucleobase portion of SEQ ID NO: 37, 38, 41, 59, 62, 63, 64, 66, 67 or 68. 
     
     
         13 . The oligonucleotide of  claim 1  which is targeted to intron 7. 
     
     
         14 . The oligonucleotide of  claim 13  wherein the target site of said oligonucleotide is nucleotide 121, 122, 123, 124, 125, 126, 127, 128 or 129 of SEQ ID NO: 1. 
     
     
         15 . The oligonucleotide of  claim 13 , wherein the nucleotide sequence of said oligonucleotide comprises at least an 8-nucleobase portion of SEQ ID NO: 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 91 or 93. 
     
     
         16 . A method of promoting inclusion of exon 7 in SMN2 transcripts in a cell, tissue or organ, comprising contacting said cell, tissue or organ with the antisense oligonucleotide of  claim 1 . 
     
     
         17 . The method of  claim 16  wherein said oligonucleotide is targeted to an intronic splicing silencer element. 
     
     
         18 . The method of  claim 16  wherein said oligonucleotide is targeted to an exonic splicing silencer element. 
     
     
         19 .- 22 . (canceled) 
     
     
         23 . A pharmaceutical composition comprising the antisense oligonucleotide of  claim 1 .