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Antisense induced redirection of splicing: Will duchenne muscular dystrophy be the thin edge of the wedge?

Wilton, S.D. and Fletcher, S. (2005) Antisense induced redirection of splicing: Will duchenne muscular dystrophy be the thin edge of the wedge? In: 4th Australasian Gene Therapy Society Meeting, 27 - 29 April 2005, Rydges Hotel, Carlton, VIC.


Alternative splicing is a major source of diversity of gene expression. Multiple products, some of which have antagonistic activities, are generated from the same gene. Redirecting gene expression through antisense oligonucleotide (AO)-induced modification of splicing patterns could be applied to a range of conditions including: (a) correcting gene defects arising from splicing mutations, (b) by-passing serious disease-causing mutations through induced exon skipping, and (c) redirecting gene transcript splicing patterns as a potential anticancer therapy. We are evaluating the potential of AOs to by-pass defects in the dystrophin gene that preclude the synthesis of a functional protein and result in the severe Duchenne muscular dystrophy. In-frame dystrophin gene re-arrangements typically result in a milder form of muscular dystrophy, clearly demonstrating that some regions of the dystrophin protein can be lost with relatively minor consequences. The huge size of the dystrophin gene, its complex expression patterns and the fact that the predominant isoforms are expressed in nondividing cells, have hindered gene replacement therapies for DMD, but render the dystrophin gene an ideal candidate to evaluate AO therapies directed at splicing intervention. An international consortium between researchers in the Netherlands, United Kingdom and Australia is planning clinical trials to evaluate AO intervention in DMD. In a relatively short space of time, exon skipping has progressed from some interesting in vitro experiments to the planned commencement of first-time-in-human trials later this year. Despite much optimism in this area, caution must be advised. Exon skipping cannot ‘‘cure’’ DMD but may reduce the severity; exon skipping cannot be applied to all cases of DMD and complete coverage of many dystrophin mutations would require a large battery of different AOs. Each AO must be regarded as a different drug and the extensive safety and toxicology testing will be a massive undertaking that must be addressed.

Item Type: Conference Item
Notes: Plenary
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