Journal article
By-passing the nonsense mutation in the 4CV mouse model of muscular dystrophy by induced exon skipping
The Journal of Gene Medicine, Vol.11(1), pp.46-56
2009
Abstract
BACKGROUND:
Duchenne muscular dystrophy (DMD), a severe neuromuscular disorder, is caused by protein-truncating mutations in the dystrophin gene. Absence of functional dystrophin renders muscle fibres more vulnerable to damage and necrosis. We report antisense oligomer (AO) induced exon skipping in the B6Ros.Cg-Dmd(mdx-4Cv)/J (4(CV)) mouse, a muscular dystrophy model arising from a nonsense mutation in dystrophin exon 53. Both exons 52 and 53 must be excised to remove the mutation and maintain the reading frame.
METHODS:
A series of 2'-O-methyl modified oligomers on a phosphorothioate backbone (2OMeAOs) were designed and evaluated for the removal of each exon, and the most effective compounds were then combined to induce dual exon skipping in both myoblast cultures and in vivo. Exon skipping efficiency of 2OMeAOs and phosphorodiamidate morpholino oligomers (PMOs) was evaluated both in vitro and in vivo at the RNA and protein levels.
RESULTS:
Compared to the original mdx mouse studies, induction of exon skipping from the 4(CV) dystrophin mRNA was far more challenging. PMO cocktails could restore synthesis of near-full length dystrophin protein in cultured 4(CV) myogenic cells and in vivo, after a single intramuscular injection.
CONCLUSIONS:
By-passing the protein-truncating mutation in the 4(CV) mouse model of muscular dystrophy could not be achieved with single oligomers targeting both exons and was only achieved after the application of AO cocktails to remove exons 52 and 53. As in previous studies, the stability and efficiency of PMOs proved superior to 2OMeAOs for consistent and sustained protein induction in vivo.
Details
- Title
- By-passing the nonsense mutation in the 4CV mouse model of muscular dystrophy by induced exon skipping
- Authors/Creators
- C. Mitrpant (Author/Creator) - The University of Western AustraliaS. Fletcher (Author/Creator) - The University of Western AustraliaP.L. Iversen (Author/Creator) - Sarepta Therapeutics (United States)S.D. Wilton (Author/Creator) - The University of Western Australia
- Publication Details
- The Journal of Gene Medicine, Vol.11(1), pp.46-56
- Publisher
- Wiley
- Identifiers
- 991005542740207891
- Copyright
- © 2008 John Wiley & Sons, Ltd
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental
- ESI research areas
- Molecular Biology & Genetics