Antisense polynucleotides to induce exon skipping and method of treating dystrophies

Abstract

Antisense polynucleotides and their use in pharmaceutical compositions to induce exon skipping in targeted exons of the gamma sarcoglycan gene are provided, along with methods of preventing or treating dystrophic diseases such as Limb-Girdle Muscular Dystrophy.

What is claimed is: 
     
         1 . An isolated antisense polynucleotide wherein the polynucleotide specifically hybridizes to an exon target region of a gamma sarcoglycan RNA, wherein the exon is selected from the group consisting of exon 4 (SEQ ID NO: 1), exon 5 (SEQ ID NO: 2), exon 6 (SEQ ID NO: 3), exon 7 (SEQ ID NO: 4) and a combination thereof. 
     
     
         2 . The antisense polynucleotides of  claim 1 , wherein the polynucleotide cannot form an RNase H substrate. 
     
     
         3 . The antisense polynucleotide of  claim 1  or  claim 2 , comprising a modified polynucleotide backbone. 
     
     
         4 . The antisense polynucleotide of any one of  claims 1 - 3 , wherein the modified polynucleotide backbone comprises a modified moiety substituted for the sugar of at least one of the polynucleotides. 
     
     
         5 . The antisense polynucleotide of  claim 5 , wherein the modified moiety is a Morpholino. 
     
     
         6 . The antisense polynucleotide of any one of  claims 3 - 5 , wherein the modified polynucleotide backbone of at least one of the polynucleotides comprises at least one modified internucleotide linkage. 
     
     
         7 . The antisense polynucleotide of  claim 6 , wherein the modified internucleotide linkage comprises a modified phosphate. 
     
     
         8 . The antisense polynucleotide of  claim 7 , wherein the modified phosphate is selected from the group consisting of a methyl phosphonate, a methyl phosphorothioate, a phosphoromorpholidate, a phosphoropiperazidate and a phosphoroamidate. 
     
     
         9 . The antisense polynucleotide of any one of  claims 3 - 8 , wherein the polynucleotide is a 2′-O-methyl-oligoribonucleotide. 
     
     
         10 . The antisense polynucleotide of any one of  claims 1 - 9 , wherein the polynucleotide is chemically linked to one or more conjugates that enhance the activity, cellular distribution, or cellular uptake of the antisense polynucleotide. 
     
     
         11 . A pharmaceutical composition, comprising the antisense polynucleotide of any one of  claims 1 - 10  and a physiologically compatible phosphate buffer. 
     
     
         12 . A kit comprising the antisense polynucleotide of any one of  claims 1 - 10 , optionally in a container, and a package insert, package label, instructions or other labeling.