Treatment of genetic disorders associated with dna repeat instability

Abstract

The current invention provides for methods and medicaments that apply oligonucleotide molecules complementary only to a repetitive sequence in a human gene transcript, for the manufacture of a medicament for the diagnosis, treatment or prevention of a cis-element repeat instability associated genetic disorders in humans. The invention hence provides a method of treatment for cis-element repeat instability associated genetic disorders. The invention also pertains to modified oligonucleotides which can be applied in method of the invention to prevent the accumulation and/or translation of repeat expanded transcripts in cells.

1 - 23 . (canceled) 
     
     
         24 . A method of preventing or treating in a subject, a genetic disorder associated with human cis-element repeat instability, comprising administering to the subject an oligonucleotide comprising or consisting of a sequence that is complementary only to a repetitive sequence in a gene transcript. 
     
     
         25 . The method of  claim 24 , wherein the disorder is a spino-cerebellar ataxia (SCA), spinal and bulbar muscular atrophy (SBMA), or dentatorubral-pallidoluysian atrophy (DRPLA). 
     
     
         26 . The method of  claim 24 , wherein the oligonucleotide comprises or consists of a sequence that is complementary only to a polyglutamine (CAG)n repetitive nucleotide unit. 
     
     
         27 . The method of  claim 25 , wherein the SCA is SCA type 1, 2, 3, 6, 7, or 17. 
     
     
         28 . The method of  claim 24 , wherein the oligonucleotide has a length of 10 to 50 nucleotides or 12 to 30 nucleotides. 
     
     
         29 . The method of  claim 24 , wherein the oligonucleotide is a single-stranded oligonucleotide. 
     
     
         30 . The method of  claim 24 , wherein the oligonucleotide comprises or consists of RNA nucleotides, DNA nucleotides, 2′-O substituted RNA nucleotides, locked nucleic acid (LNA) nucleotides, peptide nucleic acid (PNA) nucleotides, morpholinophosphorodiamidates, ethylene-bridged nucleic acid (ENA) nucleotides or mixtures thereof, with or without a phosphorothioate-containing backbone. 
     
     
         31 . The method of  claim 30 , wherein the oligonucleotide comprises 2′-O substituted RNA phosphorothioate nucleotides. 
     
     
         32 . The method of  claim 31 , wherein the 2′-O-substituted RNA phosphorothioate nucleotide is a 2′-O-methyl or 2′-O-methoxy ethyl RNA phosphorothioate nucleotide. 
     
     
         33 . The method of  claim 24 , wherein the oligonucleotide is provided in an expression vector. 
     
     
         34 . The method of  claim 33 , wherein the expression vector is a viral vector. 
     
     
         35 . The method of  claim 24 , wherein the oligonucleotide is provided with an excipient and/or a targeting ligand for delivery of the oligonucleotide to cells and/or for enhancing intracellular delivery of the oligonucleotide. 
     
     
         36 . The method of  claim 24 , wherein the oligonucleotide is comprised in a pharmaceutically acceptable composition. 
     
     
         37 . The method of  claim 36 , wherein the pharmaceutical composition further comprises at least one excipient and/or targeting ligand for delivery of the oligonucleotide to the cell and/or for enhancing intracellular delivery of the oligonucleotide. 
     
     
         38 . The method of  claim 24 , wherein the oligonucleotide preferentially hybridizes to a disease-associated or disease-causing transcript and leaves the function of a normal transcript relatively unaffected. 
     
     
         39 . The method of  claim 24 , wherein the oligonucleotide prevents the accumulation and/or translation of repeat expanded transcripts in cells. 
     
     
         40 . The method of  claim 39 , wherein the repeat expanded transcript is a (CAG)n repeat in an ATXN1, ATXN2, ATXN3, SCA7, CACNA1A, AR, SCA17, or DRPLA gene transcript in a cell. 
     
     
         41 . The method of  claim 24 , wherein the oligonucleotide interferes with gene expression or one or more other precursor RNA or messenger-RNA dependent cellular processes, optionally wherein the messenger-RNA-dependent cellular process is RNA splicing or exon skipping. 
     
     
         42 . The method of  claim 24 , wherein the administration is carried out by one or more parenteral injections at one or multiple sites in the human body. 
     
     
         43 . The method of  claim 42 , wherein the parenteral injection is an intravenous, a subcutaneous, an intramuscular, an intrathecal, or an intraventricular injection.