Exon skipping is recognized as the most promising molecular therapeutic for Duchenne muscular dystrophy (DMD). It involves systemic delivery of anti-sense drugs targeted to 'repair'the translational reading frame of the dystrophin mRNA. The out-of-frame Duchenne mRNA is converted into an in-frame transcript capable of producing semi-functional dystrophin protein (Becker-like dystrophins). The collaborating investigators have been instrumental in development of this approach as a rational therapeutic for DMD. AVI Biopharma, with Dr. Francesco Muntoni (University College London), conducted Phase I and II studies of an exon 51 morpholino drug (up to 20 mg/kg) in DMD and demonstrated de novo dystrophin production in muscle following treatment. Pre-clinical data suggest that higher doses may be needed. Dr. Jerry Mendell (Nationwide Children's, Columbus OH) will use the same AVI drug at 30 and 50 mg/kg for up to 24 weeks to better define the therapeutic window. Fundamental to the development of these compounds is to understand the relationship between dose/regimen and renal effects, since reversible accumulation of AO in kidney has been observed at high doses in animal studies and is dose-limiting. In this Clinical Project, we propose to collect first void urine from patients in the dose-ranging trial at Nationwide Children's Hospital (Mendell) (Aim 1). This trial will be carried out in parallel to the urine biomarker discovery Project 2, and the pre-clinical therapeutic index studies carried out in Project 3.
Aim 2 of the current project is to identify biomarkers that are instructive in monitoring morpholino accumulation in the proximal renal tubule cells, and then carry out a pilot study of these markers in the DMD patient urines banked in Aim 1.
Aim 3 is to integrate data from all three projects in the specialized center for Research in Pediatric Developmental Pharmacology (RPDP) to define optimal dosing regimens for exon skipping. The proposed research project is the clinical component of the broader U54 RPDP, where we systemically investigate the therapeutic index of high dose IV morpholino drugs. The proposed research has far-reaching implications for multiple exon-specific morpholino AO drugs in DMD, including an exon 45 drug in the DoD pre-clinical effort that Dr. Connor is leading with the short term goal to facilitate an "approval as a chemistry" regulatory strategy. If successful, the tools developed in this proposal could also be used to test the renal effects of other drugs.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-A)
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Children's Research Institute
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