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Splice intervention to treat duchenne muscular dystrophy and beyond

Wilton, S., Adams, A.M., Meloni, P., Johnsen, R., Forrest, S., Greer, K., Stone, L., Mitrpant, C. and Fletcher, S. (2009) Splice intervention to treat duchenne muscular dystrophy and beyond. In: 33rd HGSA Annual Scientific Meeting, 3 - 6 May 2009, Fremantle, Western Australia.


Clinical trials are underway to demonstrate that antisense oligomers (AOs) can redirect dystrophin gene transcript splicing to excise selected exons, and thereby remove protein truncating mutations that would otherwise lead to Duchenne muscular dystrophy (DMD). Due to the widespread and complex nature of dystrophin gene expression, DMD is a great challenge to any therapy. However, characterization of the gene structure in Becker MD patients presenting with mild phenotypes, indicate that substantial portions of the dystrophin gene can be lost with relatively minor consequences, and some in-frame deletions may only be identified late in life. It as been confirmed that over half of the 79 exons are redundant, when lost in particular combinations. While 10-12 AOs should restore the reading- frame in the more common genomic deletion hotspots, scores of AOs will be needed to by-pass the many different protein-truncating mutations spread across the gene. The immediate challenges are (i) to establish effective dosage regimens, (ii) gain acceptance for these personalized genetic medicines as class-specific compounds, (iii) extend the treatment to all potentially amenable mutations in the dystrophin gene and (iv) apply this platform to other acquired and genetic conditions.

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