Modulating Calcium Signals to Boost AON Exon Skipping for DMD
Technical Report,30 Sep 2015,29 Sep 2018
UNIVERSITY OF CALIFORNIA 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. While we were unable to see consistent skip boosting in the absences of AON, we were able to demonstrate high level of endogenous skipping in DMD iDRM which are exon 44 skippable relative to other mutations. Natural history data demonstrate slower progression, likely as a result of this low level of dystrophin expressed, These data promise to inform clinical trial design as well as elucidate mechanisms or compensatory elements that predispose to DMD self correctionrescue.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research