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Induced splice-switching to study dystrophin isoform function and expression

Fletcher, S., Adams, A.M., Greer, K., Johnsen, R. and Wilton, S.D. (2010) Induced splice-switching to study dystrophin isoform function and expression. In: OzBio, 26 September - 1 October, Melbourne, Australia.


Duchenne muscular dystrophy (DMD) is an X-linked, relentlessly progressive muscle wasting disorder with a predictable course and fatal outcome. DMD is caused by mutations in the dystrophin gene that prematurely terminate the protein, and affects 1 in 3500 male births. Although treatment options have been limited, advances in clinical care have doubled the life expectancy of affected boys over the last 2-3 decades, but do not address the primary etiology of DMD, the absence of dystrophin. Biological therapeutics are now becoming available, and antisense oligomer-mediated splice manipulation to exclude selected exons can overcome disease-causing mutations and restore dystrophin expression. We show that peptide-conjugated phosphorodiamidate morpholino oligomer induced splice-switching can also be used to alter isoform expression, or induce a frame-shift and prevent translation of functional products. Exclusion of selected exon blocks to yield in- frame transcripts can allow mapping of functional protein domains, based upon exon boundaries, and permits physiological evaluation of dystrophin isoforms to aid in the design of splice - manipulation therapies. It is also possible to efficiently disrupt the normal dystrophin mRNA reading frame and ablate dystrophin expression in wild-type mouse muscle. Total suppression of dystrophin gene expression was induced by selected exon removal and maintained for several weeks in vivo, resulting in severe dystrophic pathology in diaphragm within 4 weeks of commencing treatment in wild-type neonatal mice. Manipulating expression through altered splicing patterns could be applied to many different genes, offering the opportunity to induce transient mouse models to study the consequences of gene suppression or isoform selection in vivo.

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