RNA Modulating Oligonucleotides with Improved Characteristics for the Treatment of Duchenne and Becker Muscular Dystrophy

Abstract

The current invention provides an improved oligonucleotide and its use for treating, ameliorating, preventing and/or delaying DMD or BMD.

What is claimed is: 
     
         1 . An oligonucleotide comprising a 2′-O-methyl RNA monomer and a phosphorothioate backbone and comprising a 5-methyluracil and/or a 5-methylcytosine and/or a 2,6-diaminopurine base, wherein said oligonucleotide is represented by a nucleotide or a base sequence comprising or consisting of SEQ ID NO:216, or by a nucleotide or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:216, said oligonucleotide having a length of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 nucleotides. 
     
     
         2 . The oligonucleotide of  claim 1 , wherein the oligonucleotide comprises or consists of a sequence which is reverse complementary to and/or binds to and/or targets and/or hybridizes at least a part of dystrophin pre-mRNA exon 23. 
     
     
         3 . The oligonucleotide of  claim 1 , wherein the oligonucleotide has a base sequence comprising or consisting of SEQ ID NO:214 or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:214. 
     
     
         4 . A pharmaceutical composition, comprising the oligonucleotide of  claim 1  and an excipient. 
     
     
         5 . A method of treating DMD or BMD, comprising administering to a subject having DMD or BMD the oligonucleotide of  claim 1 . 
     
     
         6 . An oligonucleotide comprising a 2′-O-methyl RNA monomer and a phosphorothioate backbone and comprising a 5-methyluracil and/or a 5-methylcytosine and/or a 2,6-diaminopurine base, wherein said oligonucleotide is represented by a nucleotide or a base sequence comprising or consisting of SEQ ID NO:95, or by a nucleotide or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:95, said oligonucleotide having a length of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 nucleotides. 
     
     
         7 . The oligonucleotide of  claim 6 , wherein the oligonucleotide comprises or consists of a sequence which is reverse complementary to and/or binds to and/or targets and/or hybridizes at least a part of dystrophin pre-mRNA exon 44. 
     
     
         8 . The oligonucleotide of  claim 6 , wherein the oligonucleotide has a base sequence comprising or consisting of any one of SEQ ID NOS:204, 205 or 207 or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of any one of SEQ ID NOS:204, 205 or 207. 
     
     
         9 . A pharmaceutical composition, comprising the oligonucleotide of  claim 6  and an excipient. 
     
     
         10 . A method of treating DMD or BMD, comprising administering to a subject having DMD or BMD the oligonucleotide of  claim 6 . 
     
     
         11 . An oligonucleotide comprising a 2′-O-methyl RNA monomer and a phosphorothioate backbone and comprising a 5-methyluracil and/or a 5-methylcytosine and/or a 2,6-diaminopurine base, wherein said oligonucleotide is represented by a nucleotide or a base sequence comprising or consisting of SEQ ID NO:101, or by a nucleotide or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:101, said oligonucleotide having a length of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 nucleotides. 
     
     
         12 . The oligonucleotide of  claim 11 , wherein the oligonucleotide comprises or consists of a sequence which is reverse complementary to and/or binds to and/or targets and/or hybridizes at least a part of dystrophin pre-mRNA exon 45. 
     
     
         13 . The oligonucleotide of  claim 11 , wherein the oligonucleotide has a base sequence comprising or consisting of SEQ ID NO:200 or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:200. 
     
     
         14 . A pharmaceutical composition, comprising the oligonucleotide of  claim 11  and an excipient. 
     
     
         15 . A method of treating DMD or BMD, comprising administering to a subject having DMD or BMD the oligonucleotide of  claim 11 . 
     
     
         16 . An oligonucleotide comprising a 2′-O-methyl RNA monomer and a phosphorothioate backbone and comprising a 5-methyluracil and/or a 5-methylcytosine and/or a 2,6-diaminopurine base, wherein said oligonucleotide is represented by a nucleotide or a base sequence comprising or consisting of SEQ ID NO:120, or by a nucleotide or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:120, said oligonucleotide having a length of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 nucleotides. 
     
     
         17 . The oligonucleotide of  claim 16 , wherein the oligonucleotide comprises or consists of a sequence which is reverse complementary to and/or binds to and/or targets and/or hybridizes at least a part of dystrophin pre-mRNA exon 52. 
     
     
         18 . The oligonucleotide of  claim 16 , wherein the oligonucleotide has a base sequence comprising or consisting of SEQ ID NO:172 or 173 or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:172 or 173. 
     
     
         19 . A pharmaceutical composition, comprising the oligonucleotide of  claim 16  and an excipient. 
     
     
         20 . A method of treating DMD or BMD, comprising administering to a subject having DMD or BMD the oligonucleotide of  claim 16 . 
     
     
         21 . An oligonucleotide comprising a 2′-O-methyl RNA monomer and a phosphorothioate backbone and comprising a 5-methyluracil and/or a 5-methylcytosine and/or a 2,6-diaminopurine base, wherein said oligonucleotide is represented by a nucleotide or a base sequence comprising or consisting of SEQ ID NO:137, or by a nucleotide or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:137, said oligonucleotide having a length of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33 nucleotides. 
     
     
         22 . The oligonucleotide of  claim 21 , wherein the oligonucleotide comprises or consists of a sequence which is reverse complementary to and/or binds to and/or targets and/or hybridizes at least a part of dystrophin pre-mRNA exon 55. 
     
     
         23 . The oligonucleotide of  claim 21 , wherein the oligonucleotide has a base sequence comprising or consisting of SEQ ID NO:185 or a base sequence comprising or consisting of at least a 10 nucleotide contiguous fragment of SEQ ID NO:185. 
     
     
         24 . A pharmaceutical composition, comprising the oligonucleotide of  claim 21  and an excipient. 
     
     
         25 . A method of treating DMD or BMD, comprising administering to a subject having DMD or BMD the oligonucleotide of  claim 21 .