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Small chemical modulation of induced alternative splicing

Li, D., Greer, K., West, K.ORCID: 0000-0002-7036-5334, Addams, A., Fletcher, S. and Wilton, S. (2018) Small chemical modulation of induced alternative splicing. Journal of Gene Medicine, 20 (1).

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Splicing switching antisense oligonucleotides (AOs) are showing great therapeutic potential to treat inherited diseases, with Exondys 51 (a phosphorodiamidate morpholino oligomer) recently being granted accelerated approval by the US FDA for the treatment of Duchenne muscular dystrophy (DMD). The longest running clinical trial is now in its 5th year, and although there is an unequivocal increase in dystrophin after treatment, the amounts are modest and there is room for improvement. We are exploring the possibility of a combinatory therapy using the AOs and FDA approved drugs known to influence splicing. The SR protein family of splicing factors has important roles in both constitutive and alternative splicing regulations, with post‐translational modifications (phosphorylation, acetylation, methylation) of SR proteins, influencing RNA splicing. Riluzole, an FDA approved neuro‐protective drug for Amyotrophic lateral sclerosis (ALS), was reported to inhibit CDC2‐like kinases (CLK family) and disrupt the phosphorylation status of specific SR proteins that promotes the recognition of nearby 5' and 3' splice site by U1 and U2 snRNP. Our preliminary studies demonstrate that pretreatment of primary human myotubes with Riluzole can enhance 2OMeinduced exon 51 skipping in normal human primarymyogenic cells in a dosage dependent manner. Further studies are under way to further refine timing and Riluzone:AOdosages and explore the underlyingmechanism, paving the way for novel combinatory therapies to safely enhance AO induced exon skipping as a treatment for DMD.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
Publisher: John Wiley & Sons
Copyright: © 2018 John Wiley & Sons, Ltd.
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