Successful drug development requires a therapeutic regimen that is safe and maximally effective. Morpholino-mediated exon skipping has been demonstrated to achieve restoration of dystrophin in both animal models (mice and dogs) and in DMD boys in early clinical trials. In addition to efficacy, toxicity must be considered in optimizing dose selection for AO therapy. Experience with PMO-AO suggests that while these compounds have a better therapeutic index compared to other AO chemistries, renal effects are anticipated to be the primary dose limiting toxicity. Establishment of reliable and reproductive methods for pre-clinical and clinical monitoring of renal effects of morpholino AO is critical for optimal dose selection and a "class" approval regulatory strategy. Preliminary GLP toxicology studies, and non-GLP studies using high dose morpholino AO directed at exon 51 (12 wk, 960 mg/kg/wk IV murine) showed significant accumulation of the drug in kidney proximal tubule cells. However, kidney accumulation resolved once drug treatment was stopped, suggesting optimized dosing could minimize renal toxicity or that a drug "holiday" may be needed in the regimen. Here we hypothesize that establishing an appropriate therapeutic window in DMD patients will involve a balance of muscle retention of AO drug (efficacy) vs. kidney retention (toxicity). Therefore, the goal of this project is to systematically investigate the dosing schedules that achieve this balance through the following two aims.
Aim 1 will carry out 6 month chronic comparative dosing of morpholino drug in rats using iPRECIO telemetry pumps (jugular vein cannulation), with endpoints of urine and epithelial cell biochemistry (Core B), kidney histology and novel biomarkers (Project 2).
In Aim 2, we will carry out a similar IV dosing schedule in the mouse disease model (mdx), with the goal of testing drug efficacy, drug bioavailability in muscle (RT-PCR and dystrophin quantity), and kidney accumulation (Core B, and Project 2). This systematic comparison of multiple drugs in multiple species will provide an assessment of the optimized therapeutic Index. Use of morpholino AO to correct genetic defects is rapidly advancing to several other human diseases such as FSHD, Cystic fibrosis, myotonic dystrophy, LGMD etc. Therefore the efficacy and toxicity data generated from this proposal have much broader implications than treatment for Duchenne muscular dystrophy.

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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