Abstract Details

Title Evaluating Pharmacology and Efficacy of Delandistrogene Moxeparvovec in Young and Aged DMDmdx Rats

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-008

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. DMD^mdx 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) DMD^mdx rats. The older rats demonstrate a more severe phenotype in terms of fibrosis or cardiac disease progression. Rats received a dose of 1.33x10¹⁴vg/kg or 7.00x10¹³ 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 DMD^mdx 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.

Authors/Disclosures
Kaitlin Dickinson, PhD (Sarepta Therapeutics) PRESENTER	No disclosure on file
Rachael Potter	No disclosure on file
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Louise R. Rodino-Klapac (Sarepta Therapeutics)	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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