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Making sense in Duchenne muscular dystrophy: Slowing the natural progression of muscle wasting

Wilton, S. and Fletcher, S. (2017) Making sense in Duchenne muscular dystrophy: Slowing the natural progression of muscle wasting. Journal of the Neurological Sciences, 381 (Supp.). p. 58.

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Background: The most common and severe form of childhood muscle wasting, Duchenne muscular dystrophy (DMD), is caused by protein-truncating mutations that preclude functional dystrophin expression. We have shown that antisense oligomers can redirect dystrophin pre-mRNA processing to remove the mutation and restore the reading frame to allow expression of a functional dystrophin.

Objective: There are great challenges in designing clinical trials to evaluate drugs for rare diseases, especially where patient numbers are small and disease progression is slow. New clinical trial procedures must be considered.

Patients and Methods / Material and Methods: Nevertheless, Exondys 51, a phosphorodiamidate morpholino oligomer designed to excise dystrophin exon 51 from the mature mRNA, was granted accelerated approval by the US Food and Drug Administration in September, 2016.

Results: Exondys 51 is the first dystrophin restoring drug, as well as the first specific exon-skipping drug, to be approved for clinical use. There was vigorous and heated discussion within and outside the FDA after the accelerated approval of Exondys 51, and these issues will be discussed and concerns addressed. As requested by the FDA, additional phase 3 clinical trials have been initiated to evaluate skipping of other dystrophin exons (45 or 53).

Conclusion: Since most human genes undergo some form of splicing during expression, therapeutic intervention during splicing could be relevant to many inherited and acquired conditions. We are currently exploring “Therapeutic alternative splicing” as a treatment for inherited and acquired conditions, including adult onset Pompe’s disease, multiple sclerosis, spinal muscular atrophy and cystic fibrosis.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: Elsevier BV
Copyright: © 2018 Elsevier B.V.
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