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Exon skipping strategies to address DMD-Causing mutations: Personalised genetic therapies

Meloni, P., Stone, L., Fletcher, S. and Wilton, S. (2009) Exon skipping strategies to address DMD-Causing mutations: Personalised genetic therapies. In: 6th Australasian Gene Therapy Society Meeting, 29 April - 1 May 2009, Kerry Packer Education Centre. Royal Prince Alfred Hospital, Sydney, NSW.


Duchenne Muscular Dystrophy (DMD) is a severe and progressive muscle wasting disease, caused by protein truncating mutations in the dystrophin gene. Becker Muscular Dystrophy (BMD), an allelic condition is generally caused by in-frame deletions within the dystrophin gene, resulting in the production of an internally deleted but variably functional protein. Antisense-Oligomer (AO) induced-exon skipping has the potential to by-pass protein truncating mutations and restore functional dystrophin expression. We have designed and optimised a series of AOs to excise individual dystrophin exons 2 to 78 during processing of the dystrophin pre-mRNA. Here we describe exon skipping strategies to rescue dystrophin expression in patient cell lines where more than one exon-skipping strategy may restore the reading frame. A genomic deletion of exon 44 may be addressed by the excision of exons 43 or 45. The resultant dystrophin isoforms may have different functionality. A splice acceptor defect in exon 21 leads to disruption of the reading frame, and this may be restored by one of three different strategies. It will be crucial to identify which AO treatment will result in themost functional dystrophin isoform for those cases where more than one treatment option is applicable.

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