Antisense oligo-mediated multiple exon skipping in a dog model of duchenne muscular dystrophy

Methods Mol Biol. 2011;709:299-312. doi: 10.1007/978-1-61737-982-6_20.

Abstract

Exon skipping is currently one of the most promising molecular therapies for Duchenne muscular -dystrophy (DMD). We have recently developed multiple exon skipping targeting exons 6 and 8 in -dystrophin mRNA of canine X-linked muscular dystrophy (CXMD), an animal model of DMD, which exhibits severe dystrophic phenotype in skeletal muscles and cardiac muscle. We have induced efficient exon skipping both in vitro and in vivo by using cocktail antisense 2'O-methyl oligonucleotides (2'OMePS) and cocktail phosphorodiamidate morpholino oligomers (morpholinos, or PMOs) and ameliorated phenotype of dystrophic dogs by systemic injections. The multiple exon skipping (double exon skipping) shown here provides the prospect of choosing deletions that optimize the functionality of the truncated dystrophin protein for DMD patients by using a common cocktail that could be validated as a single drug and also potentially applicable for more than 90% of DMD patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • Disease Models, Animal
  • Dogs
  • Dystrophin / genetics
  • Exons
  • Genetic Therapy / methods*
  • Morpholines / therapeutic use*
  • Morpholinos
  • Muscle, Skeletal
  • Muscular Dystrophy, Animal / genetics*
  • Muscular Dystrophy, Animal / therapy*
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / therapy
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / therapeutic use
  • Phenotype
  • Reading Frames

Substances

  • Dystrophin
  • Morpholines
  • Morpholinos
  • Oligonucleotides, Antisense