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Modulating Calcium Signals to Boost AON Exon Skipping for DMD

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Technical Report,30 Sep 2016,29 Sep 2017

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University of California, Los Angeles Los Angeles United States

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AON-mediated exon skipping is currently advancing as therapy for DMD, though levels of dystrophin produced remains suboptimal. Thus, identification of compounds with the capacity to boost exon skipping could help fully realize this potentially life-changing DMD treatment. We have assessed whether dantrolene, an already FDA-approved drug, can boost efficacy of AON exon skipping in the context of AON targeting skipping of exons 51, 44 or 45. Additionally, we have begun testing proprietary compounds that regulate the same Ca2 pathway regulated by dantrolene for skip-boosting. As a second objective we are assessing these compounds for their ability promote exon skipping in patient cells with DMD mutations that have a low level endogenous skipping, dystrophin expression andor mild phenotypes. Preliminary data indicate that these compounds are effective in at least a subset of patient cell models one candidate may boost skipping even better than dantrolene. Based on its known activity, this compound promises greater efficacy and a wider therapeutic window than dantrolene. Planned studies will combine chemical genomics with RNA Seq analysis to identify mechanisms of activity and specificity in order to guide discovery of second-generation skipping drugs or combinations with greater activity.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology
  • Biochemistry

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