Oligonucleotide comprising an inosine for treating dmd

Abstract

The invention provides an oligonucleotide comprising an inosine, and/or a nucleotide containing a base able to form a wobble base pair or a functional equivalent thereof, wherein the oligonucleotide, or a functional equivalent thereof, comprises a sequence which is complementary to at least part of a dystrophin pre-m RNA exon or at least part of a non-exon region of a dystrophin pre-m RNA said part being a contiguous stretch comprising at least 8 nucleotides. The invention further provides the use of said oligonucleotide for preventing or treating DMD or BMD.

1 . An isolated oligonucleotide comprising a sequence which is complementary to at least part of a dystrophin pre-mRNA exon or at least part of a non-exon region of a dystrophin pre-mRNA said part being a contiguous stretch comprising at least 8 nucleotides, wherein said oligonucleotide comprises one or both of an inosine nucleotide and a nucleotide containing a base able to form a wobble base pair with a complementary base to which it is paired. 
     
     
         2 . An isolated oligonucleotide according to  claim 1 , wherein the contiguous stretch comprises between 13 and 50 nucleotides, of RNA of an exon of a dystrophin pre-mRNA. 
     
     
         3 . An isolated oligonucleotide according to  claim 2 , wherein said exon comprises exon 51, 45, 53, 44, 46, 52, 50, 43, 6, 7, 8, 55, 2, 11, 17, 19, 21, 57, 59, 62, 63, 65, 66, 69, and/or 75. 
     
     
         4 . (canceled) 
     
     
         5 . An isolated oligonucleotide according to  claim 1 , wherein the oligonucleotide comprises a first part and a second part, wherein said first part comprises least 8, consecutive nucleotides that are complementary to a first exon and wherein said second part comprises at least 8 consecutive nucleotides that are complementary to a second exon in said dystrophin pre-mRNA. 
     
     
         6 . An isolated oligonucleotide according to  claim 5 , wherein said first and said second exon are separated in said dystrophin pre-mRNA by at least one exon to which said oligonucleotide is not complementary. 
     
     
         7 . An oligonucleotide according to  claim 5 , wherein said first and said second exon are contiguous in said dystrophin pre-mRNA. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A composition comprising at least two distinct oligonucleotides as defined in  claim 1 . 
     
     
         12 . A composition according to  claim 11 , wherein each said distinct oligonucleotide is dosed, independently, in an amount between 0.5 mg/kg and 10 mg/kg, inclusive. 
     
     
         13 . A composition according to  claim 11  in combination with one or more of:
 (a) an adjunct compound for reducing inflammation, preferably for reducing muscle tissue inflammation, 
 (b) an adjunct compound for improving muscle fiber function, integrity and/or survival, and 
 (c) a compound exhibiting readthrough activity. 
 
     
     
         14 . (canceled) 
     
     
         15 . A method for alleviating one or more symptom(s) of Duchenne Muscular Dystrophy or Becker Muscular Dystrophy in an individual, the method comprising administering to said individual a composition as defined in  claim 11 . 
     
     
         16 . An isolated oligonucleotide according to  claim 2  wherein said contiguous stretch comprises between 14 and 25 nucleotides of RNA of an exon of a dystrophin pre-mRNA. 
     
     
         17 . An isolated oligonucleotide according to  claim 1 , wherein the oligonucleotide comprises RNA. 
     
     
         18 . An isolated oligonucleotide according to  claim 17 , wherein said RNA comprises a modified ribonucleotide. 
     
     
         19 . An isolated oligonucleotide according to  claim 18 , wherein said modified ribonucleotide is a 2′-O-methyl modified ribose (RNA). 
     
     
         20 . An isolated oligonucleotide according to  claim 1 , comprising a modified deoxyribose (DNA) base. 
     
     
         21 . An isolated oligonucleotide according to  claim 1 , wherein said oligonucleotide comprises a peptide nucleic acid, a locked nucleic acid, a morpholino phosphorodiamidate, or a combination thereof. 
     
     
         22 . An isolated oligonucleotide according to  claim 21 , comprising a morpholino phosphorodiamidate. 
     
     
         23 . An isolated oligonucleotide according to  claim 5 , wherein said first part and said second part, independently, comprise between 16 and 80 consecutive nucleotides, inclusive. 
     
     
         24 . The composition of  claim 11 , admixed with a pharmaceutically acceptable carrier, adjuvant, diluent and/or excipient. 
     
     
         25 . The composition of  claim 13 , wherein said adjunct composition for reducing inflammation reduces tissue inflammation. 
     
     
         26 . The method of  claim 15 , wherein the composition administered provides the individual with a functional dystrophin protein. 
     
     
         27 . The method of  claim 15 , wherein the composition administered decreases the production of an aberrant dystrophin protein. 
     
     
         28 . The method of  claim 15 , wherein the composition administered increases the production of a functional or a more functional dystrophin protein. 
     
     
         29 . The method of  claim 15 , wherein the composition administered alleviates one or more symptom(s).