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Splice-modifying antisense oligomers: Precision medicines to correct aberrant splicing

Fletcher, S., Greer, K. and Wilton, S. (2015) Splice-modifying antisense oligomers: Precision medicines to correct aberrant splicing. The Journal of Gene Medicine, 17 (8-9). O16.

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Antisense oligomer‐mediated exon skipping can restore functional dystrophin expression in Duchenne muscular dystrophy (DMD), with consequent clinical benefit in a subset of patients. The most common DMD‐causing mutations are frame‐shifting deletions of one or more exons, and all clinical studies to date are designed to treat such deletions. We are extending the application of antisense oligomers to less common mutations that impact upon pre‐mRNA splicing, including splice site mutations, deep intronic changes activating cryptic exons and small mutations impacting exon selection. Many such mutations are not readily identified during routine diagnostics but may allow expression of near‐normal proteins after splice intervention. Such strategies have potential application to selected mutations in almost any gene, and are of particular interest as therapies for rare diseases, of which there are approximately 7000. Eighty percent of rare diseases are genetic in origin and, although each disease has a low incidence, collectively, these conditions present a significant burden in terms of mortality, quality of life and healthcare costs. Treatment options for rare diseases are limited, and implementation of clinical trials for rare diseases is often hindered because of low patient numbers, particularly when the treatments are mutation‐specific. Over 25% of all missense and nonsense mutations are predicted to alter pre‐mRNA processing and, together with mutations affecting canonical splice sites, are a major cause of human disease. We present strategies to address specific splicing defects, and propose an approach to develop therapeutic compounds for rare inherited diseases that would otherwise be considered beyond the scope of commercial pharmaceutical intervention.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: Wiley
Copyright: © 2015 John Wiley & Sons, Ltd.
Other Information: Oral presentation given @ Ninth Australasian Gene and Cell Therapy Society Meeting, University of Melbourne, Parkville, VIC 29 April - 1 May 2015
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