Systemic delivery of antisense oligonucleotides to drive exon skipping, and restoration of dystrophin expression, has the most promise as a therapeutic for the majority of Duchenne muscular dystrophy (DMD) patients. Similar approaches are also in early stage development for SMA and myotonic dystrophy. A challenge with the exon skipping approach for DMD is the requirement for many distinct drugs targeting different exons. Indeed, exon skipping is being considered by the FDA as an early example of personalized medicine, where drug development is optimized for the specific patient genetic code. This complicates the drug development process, greatly increasing potential cost and time required for diminishing numbers of DMD patients. An alternative approach, used for flu vaccines, is approval 'as a class'. The initial three AO drugs applicable to the greatest number of patients are exons 45, 51, and 53. Once safety and efficacy is proven with these three exon-specific drugs, approval of exon skipping as a class may facilitate drug approvals for less common exons. In this project, we propose a systematic opfimization of AO drugs for exons 45, 51, and 53. Multiple in vitro and in vivo experimental systems will be utilized to validate potency of each drug. Part of the development process for axon 45 is currently funded by a NIH UOl to the PI of this project;this funded program will be extended to patient cell studies from Project 3 and Core C. For exons 51, and 53, the entire drug development process will be funded by the proposed research program. The last aim conducts a 6 month functional efficacy study of the truncated dystrophins in dystrophin-deficient mice lacking exon 52, and will test drugs optimized for both exons 51 and 53.

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Children's Research Institute
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