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 . An 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 repetitive element having as its repetitive nucleotide unit, said repetitive nucleotide unit is selected from the list consisting of (CAG)n, (GCG)n, (CGG)n, (GAA)n, (GCC)n, (CCG)n, (AUUCU)n, (GGGGCC)n and (CCUG)n. 
     
     
         2 . An oligonucleotide according to  claim 1  which is able to hybridize to a (CAG) n repeat, 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. 
     
     
         3 . An oligonucleotide according to  claim 2 , wherein each X is 5-methylcytosine and/or each Y is 5-methyluracil. 
     
     
         4 . An oligonucleotide according to  claim 3 , wherein m is 7, preferably 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). 
     
     
         5 . An oligonucleotide according to  claim 1 , wherein the base sequence of said oligonucleotide comprises or consists of any of the base sequences SEQ ID NOS: 90-118. 
     
     
         6 . An oligonucleotide consisting of 2′-O-methyl RNA nucleotide residues, wherein said oligonucleotide comprises a backbone wherein all phosphate moieties are replaced by phosphorothioate moieties, said oligonucleotide further comprising a base sequence consisting of (SEQ ID NO:90). 
     
     
         7 . An oligonucleotide according to  claim 6 , wherein said oligonucleotide comprises a 5-methylcytosine and/or a 5-methyluracil base. 
     
     
         8 . An oligonucleotide according to  claim 7 , wherein said oligonucleotide comprises a 2, 6-diaminopurine base. 
     
     
         9 . An oligonucleotide according to  claim 8 , wherein said oligonucleotide has an improved parameter by comparison to a corresponding oligonucleotide comprising a 2′-O-methyl RNA nucleotide residue and 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. 
     
     
         10 . An oligonucleotide according to  claim 1 , wherein the length of said oligonucleotide is between 12 and 36 nucleotides. 
     
     
         11 . An oligonucleotide according to  claim 1 , wherein said oligonucleotide is a single stranded oligonucleotide. 
     
     
         12 . A composition comprising an oligonucleotide according to  claim 1 . 
     
     
         13 . A composition according to  claim 12 , said composition further comprising at least one excipient for enhancing the targeting and/or delivery of said composition to a tissue and/or cell and/or into a tissue and/or cell. 
     
     
         14 . A method for preventing, treating, and/or delaying a human cis-element repeat instability associated genetic disorder by administering an oligonucleotide according to  claim 13  to a subject in need thereof. 
     
     
         15 . A method for preventing, treating, and/or delaying a human cis-element repeat instability associated genetic disorder by administering a composition according to  claim 13  to a subject in need thereof.