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Transient mouse models for the preclinical evaluation of therapeutic dystrophin exon skipping strategies

Fletcher, S., Adams, A.M., Adkin, C., Greer, K., Johnsen, R. and Wilton, S. (2011) Transient mouse models for the preclinical evaluation of therapeutic dystrophin exon skipping strategies. In: 7th Australasian Gene Therapy Society Meeting, 4 - 6 May 2011, University of Melbourne, Melbourne.


Mutations that ablate dystrophin expression lead to Duchenne muscular dystrophy (DMD) an X-linked, relentlessly progressive muscle wasting disorder with a predictable course and limited treatment options. Corticosteroids are effective in stabilizing muscle strength in the short term but do not address the primary etiology of DMD, the absence of dystrophin. The majority of DMD cases are caused by frame-shifting deletions of one or dystrophin exons, while in-frame deletions generally cause the milder allelic disorder, Becker muscular dystrophy (BMD). Antisense oligomer (AO)-mediated splicing manipulation can exclude exons during transcript processing and by-pass DMD-causing mutations to generate shorter, partially functional BMD-like dystrophin isoforms, and is showing promise as a therapy for DMD. Dystrophin genes in selected BMD patients indicate templates for functional dystrophin isoforms, however, in-frame deletions in some regions of the dystrophin gene, particularly downstrean of exon 55 are rare, and the consequences of exon exclusion in this region are unknown. The mdx mouse is a widely used dystrophinopathy model and has a nonsense mutation in dystrophin exon 23. AO induced-excision of this exon from the mRNA removes the mutation without disrupting the reading frame, resulting in functional dystrophin expression and amelioration of the phenotype. We now report that systemic administration of AO combinations to wild-type mice can remove dystrophin exons to generate DMD- and BMD-like dystrophin isoforms for functional evaluation. Assessment of contractile properties of the muscle reveals that some in-frame exon combinations confer near normal function, while others result in muscle susceptible to contraction-induced damage.

Item Type: Conference Item
Notes: Oral presentation
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