Antisense oligonucleotides for the treatment of leber congenital amaurosis

Abstract

The present invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Leber congenital amaurosis.

1 .- 15 . (canceled) 
     
     
         16 . A method for restoring CEP290 protein function in a cell carrying the intronic CEP290 founder mutation c.2991+1655A>G, by excluding the aberrant 128 nucleotide exon from the CEP290 mRNA, said method comprising contacting said cell with an antisense oligonucleotide which is substantially complementary to a target nucleotide sequence in the CEP290 pre-mRNA, wherein said target nucleotide sequence is an Exon Splicing Enhancer (ESE) sequence, or wherein said target nucleotide sequence comprises the cryptic donor splice site created by said mutation. 
     
     
         17 . A modified antisense oligonucleotide which induces skipping of the aberrant 128 nucleotide CEP290 exon caused by the c.2991+1655A>G mutation in the CEP290 gene, wherein said oligonucleotide is substantially complementary to a target nucleotide sequence in the CEP290 pre-mRNA, wherein said target nucleotide sequence is an Exon Splicing Enhancer (ESE) sequence, or wherein said target nucleotide sequence comprises the cryptic donor splice site created by said mutation. 
     
     
         18 . A method for the treatment of Leber congenital amaurosis in an individual in need thereof, wherein the Leber congenital amaurosis is caused by the c.2991+1655A>G mutation in the CEP290 gene, said method comprising the step of excluding the aberrant 128 nucleotide exon from the CEP290 mRNA by contacting a cell of said individual with an antisense oligonucleotide that is substantially complementary to a target nucleotide sequence in the CEP290 pre-mRNA, wherein said target nucleotide sequence is an Exon Splicing Enhancer (ESE) sequence, or wherein said target nucleotide sequence comprises the cryptic donor splice site created by said mutation. 
     
     
         19 . A pharmaceutical composition comprising a modified antisense oligonucleotide which induces skipping of the aberrant 128 nucleotide CEP290 exon caused by the c.2991+1655A>G mutation in the CEP290 gene, wherein said oligonucleotide is substantially complementary to a target nucleotide sequence in the CEP290 pre-mRNA, wherein said target nucleotide sequence is an Exon Splicing Enhancer (ESE) sequence, or wherein said target nucleotide sequence comprises the cryptic donor splice site created by said mutation, and a pharmaceutically or physiologically acceptable carrier. 
     
     
         20 . The method according to  claim 16 , wherein the antisense oligonucleotide comprises a 2′-O-methyl ribose with a phosphorothioate backbone. 
     
     
         21 . The modified antisense oligonucleotide according to  claim 17 , wherein the modification comprises a 2′-O-methyl ribose with a phosphorothioate backbone. 
     
     
         22 . The method according to  claim 18 , wherein the oligonucleotide comprises a 2′-O-methyl ribose with a phosphorothioate backbone. 
     
     
         23 . The pharmaceutical composition according to  claim 19 , wherein the modification comprises a 2′-O-methyl ribose with a phosphorothioate backbone. 
     
     
         24 . The method according to  claim 16 , wherein the antisense oligonucleotide has a length from 12 to 60 nucleotides. 
     
     
         25 . The modified antisense oligonucleotide according to  claim 17 , wherein the oligonucleotide has a length from 12 to 60 nucleotides. 
     
     
         26 . The method according to  claim 18 , wherein the antisense oligonucleotide has a length from 12 to 60 nucleotides. 
     
     
         27 . The pharmaceutical composition according to  claim 19 , wherein the antisense oligonucleotide has a length from 12 to 60 nucleotides.