An investigational AAV8 gene therapy coding for a novel microdystrophin as a treatment for Duchenne Muscular Dystrophy


Clinical Trials

Poster Number: 162


Jahannaz Dastgir, DO, Regenxbio

RGX-202 is an investigational one-time gene therapy for the treatment of Duchenne Muscular Dystrophy (Duchenne) that utilizes a NAV AAV8 vector, a muscle specific promoter (Spc5-12), and an optimized microdystrophin transgene. The microdystrophin coding sequence involves codon optimization, depletion of CpG dinucleotides, and uniquely an extended coding region for the C-Terminal (CT) domain found in naturally occurring dystrophin. Preclinical studies in mdx mice demonstrated a dose proportional increase of RGX-202 vector DNA and microdystrophin in skeletal and heart muscle and restoration of the dystrophin-associated complex (DAPC) at the sarcolemma, indicating the potential benefit of the CT domain. Moreover, after a single intravenous (IV) injection of RGX-202, mdx mice showed significant improvements in dystrophic muscle pathology (muscle fibrofatty replacement and endomysial fibrosis) and function (in vitro force and automated gait analysis) at doses > 1×1014 GC/kg. A Phase I/II trial, AFFINITY DUCHENNETM, is a multicenter, open-label, dose escalation study to evaluate the safety, tolerability, and clinical efficacy of a one-time IV dose of RGX-202 in patients with Duchenne. Six ambulatory, pediatric patients (ages 4 to 11 years old) with Duchenne are expected to enroll in 2 cohorts at doses of 1×1014 genome copies (GC)/kg body weight (n=3) and 2×1014 GC/kg body weight (n=3). An expansion may allow for up to 6 additional participants to be enrolled at each dose for a total of up to 9 participants at each dose and 18 participants in the study. Key inclusion criteria are dystrophin gene mutations in exons 18 and above, performance time to stand, ability to complete 100m walk, and AAV8 seronegative status. Endpoints include safety, immunogenicity assessments, RGX-202 microdystrophin levels in muscle, functional assessments (North Star Ambulatory Assessment and timed function tests), and muscle tissue preservation (muscle MRI).