Evaluating Pharmacology and Efficacy of Delandistrogene Moxeparvovec in Young and Aged DMDmdx Rats (P3-8.008)

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Objective: The purpose of this preclinical study is to evaluate the myocardial efficacy and safety of intended commercial process delandistrogene moxeparvovec (SRP-9001) material in Duchenne muscular dystrophy (DMD)mdx rats. DMDmdx rats are a valuable alternative animal model of DMD, as they demonstrate cardiac dysfunction that recapitulates cardiac dysfunction of patients with DMD. Background: Gene transfer therapy is a promising treatment for patients with DMD. Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. Design/Methods: We performed systemic, intravenous delivery of intended commercial process delandistrogene moxeparvovec material in young (21–35 days old) and aged (3–5 months old) DMDmdx rats. The older rats demonstrate a more severe phenotype in terms of fibrosis or cardiac disease progression. Rats received a dose of 1.33×1014 vg/kg or 7.00×1013 vg/kg. Ambulation activity was recorded via the Photobeam Activity System Open Field. Echocardiograms and histological analysis of fibrosis were used to evaluate cardiac disease. Results: Data from 12 weeks and 24 weeks post-systemic delivery demonstrated no evidence of cardiac toxicity. Importantly, there were no deaths attributed to treatment. Compared with the saline control, intended commercial process delandistrogene moxeparvovec material increased ambulation and vertical activity in young DMDmdx rats and improved cardiac function. Protein expression was broadly distributed across skeletal muscle, the diaphragm and the heart. Conclusions: Taken together, these findings confirm expression in cardiac muscle of rats, as expected, and support the potential myocardial efficacy and safety of delandistrogene moxeparvovec. Further results of cardiac disease phenotypes at 12 and 24 weeks post-systemic delivery utilizing several indicators of cardiac function will also be presented. Disclosure: Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Christopher Wier has received personal compensation for serving as an employee of Sarepta Therapeutics. Christopher Wier has stock in Sarepta Therapeutics. Dr. Cooper-Olson has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Cooper-Olson has stock in Sarepta Therapeutics. Ms. Wheeler has nothing to disclose. Miss Anderbery has nothing to disclose. Ms. Kempton has received personal compensation for serving as an employee of Sarepta Therapeutics. Ms. Kempton has stock in Sarepta Therapeutics. Ms. Clements has received personal compensation for serving as an employee of Sarepta Therapeutics . Ms. Clements has stock in Sarepta Therapeutics. Mrs. Adegboye has nothing to disclose. Dr. Haile has nothing to disclose. Ms. Peterson has nothing to disclose. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

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