Rna modulating oligonucleotides with improved characteristics for the treatment of neuromuscular disorders

Abstract

The current invention provides an improved oligonucleotide and its use for treating, ameliorating, preventing, delaying and/or treating a human cis-element repeat instability associated genetic neuromuscular or neurodegenerative disorder.

1 - 15 . (canceled) 
     
     
         16 . A method for treating, delaying, ameliorating and/or preventing a human cis-element repeat instability associated genetic disorder in a subject, comprising providing to the subject an antisense oligonucleotide comprising a 2′-O-methyl RNA nucleotide residue, having a backbone wherein at least one phosphate moiety is replaced by a phosphorothioate moiety, and comprising one or more 5-methylpyrimidine and/or one or more 2,6-diaminopurine bases, wherein said oligonucleotide is able to hybridize to a (CAG) n  or (GAA) n  repetitive nucleotide unit. 
     
     
         17 . The method of  claim 16 , wherein the human cis-element repeat instability associated genetic disorder is a spinocerebellar ataxia (SCA), spinal and bulbar muscular atrophy (SBMA), or dentatorubral-pallidoluysian atrophy (DRPLA). 
     
     
         18 . The method of  claim 16 , wherein said oligonucleotide comprises or consists of a repetitive nucleotide unit (XYG) m , wherein m is an integer from 4 to 12 and each X is C or 5-methylcytosine, and each Y is U or 5-methyluracil, wherein at least one X is 5-methylcytosine and/or at least one Y is 5-methyluracil. 
     
     
         19 . The method of  claim 18 , wherein said oligonucleotide is such that each X is 5-methylcytosine and/or each Y is 5-methyluracil. 
     
     
         20 . The method of  claim 18 , wherein said oligonucleotide is such that m is 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12. 
     
     
         21 . The method of  claim 20 , wherein said oligonucleotide comprises or consists of a repetitive nucleotide unit (XYG) 7 , wherein each X is 5-methylcytosine and each Y is a uracil (SEQ ID NO: 2), or each X is a cytosine and each Y is 5-methyluracil (SEQ ID NO:3). 
     
     
         22 . The method of  claim 20 , wherein said oligonucleotide is such that m is 7. 
     
     
         23 . The method of  claim 21 , wherein the sequence of said oligonucleotide comprises or consists of any of SEQ ID NO: 90-118. 
     
     
         24 . The method of  claim 23 , wherein the base sequence of said oligonucleotide comprises or consists of SEQ ID NO:90. 
     
     
         25 . The method of  claim 16 , wherein said oligonucleotide is a single-stranded oligonucleotide. 
     
     
         26 . The method of  claim 16  wherein said oligonucleotide has a length of from 12 to 36 nucleotides. 
     
     
         27 . The method of  claim 16 , wherein said oligonucleotide remain in association to its target when there are up to 20% of mismatched nucleotides. 
     
     
         28 . The method of  claim 16 , wherein said oligonucleotide is at least 90% reverse complementary with said repetitive nucleotide unit. 
     
     
         29 . The method of  claim 16 , wherein said oligonucleotide has an improved parameter by comparison to a corresponding oligonucleotide comprising a 2′-O-methyl RNA nucleotide residue and having a backbone wherein at least one phosphate moiety is replaced by a phosphorothioate moiety, without a 5-methylcytosine, and/or a 5-methyluracil and/or a 2,6-diaminopurine. 
     
     
         30 . The method of  claim 16 , wherein said oligonucleotide reduces a detectable amount of mutant transcript and/or reduces the translation of said mutant transcript and thus the amount of mutant protein. 
     
     
         31 . The method of  claim 30 , wherein said reduction of mutant protein reduces protein aggregates in nucleus and/or cytoplasm. 
     
     
         32 . The method of  claim 16 , wherein said oligonucleotide is present in a composition. 
     
     
         33 . The method of  claim 32 , wherein said composition comprises at least one excipient that may further aid in enhancing the targeting and/or delivery of said composition and/or said oligonucleotide to a tissue and/or cell and/or into a tissue and/or cell. 
     
     
         34 . The method of  claim 16 , wherein said oligonucleotide preferentially hybridizes to a disease-associated or disease-causing transcript and leaves a function of a normal transcript relatively unaffected. 
     
     
         35 . The method of  claim 16 , wherein said subject has DRPLA, SBMA, or SCA type 1, 2, 3, 6, 7, 12 or 17. 
     
     
         36 . The method of  claim 35 , wherein said SCA type 1 is caused by CAG repeat expansions in the transcripts of ATXN1 (SEQ ID NO:81), said SCA type 2 is caused by CAG repeat expansions in the transcripts of ATXN2 (SEQ ID NO: 82), said SCA type 3 is caused by CAG repeat expansions in the transcripts of ATXN3 (SEQ ID NO: 83), said SCA type 6 is caused by CAG repeat expansions in the transcripts of CACNA1A (SEQ ID NO:84), said SCA type 7 is caused by CAG repeat expansions in the transcripts of ATXN7 (SEQ ID NO: 85), said SCA type 12 is caused by CAG repeat expansions in the transcripts of PPP2R2B (SEQ ID NO: 86), and said SCA type 17 is caused by CAG repeat expansions in the transcripts of TBP (SEQ ID NO: 87) genes. 
     
     
         37 . The method of  claim 16 , wherein said SBMA is caused by CAG repeat expansions in the transcripts of AR (SEQ ID NO: 88), and said DRPLA is caused by CAG repeat expansions in the transcripts of ATN1 (SEQ ID NO: 89) genes.