AAV-mediated gene transfer of a novel microdystrophin ameliorates pathology and enhances muscle function in a mouse model of DMD.

Use of adeno-associated virus (AAV)-mediated transfer of functional microdystrophins to address Duchenne muscular dystrophy (DMD) has been established. RGX-202, an AAV8 vector encoding a novel, optimized human microdystrophin with an extended C-terminal domain, expressed under the Spc5-12 muscle-specific promoter, was evaluated for tolerability and efficacy in dystrophin-deficient mdx mouse in 12- and 26-week studies at vector doses ranging from 3 × 1013 to 5 × 1014 gc/kg. A single intravenous administration of RGX-202 was well tolerated and led to robust, dose-dependent expression of microdystrophin in skeletal and cardiac muscles at 12 weeks, which persisted to 26 weeks post-administration. Increased microdystrophin was associated with recruitment of the dystrophin-associated protein complex to the sarcolemma, particularly at doses ≥1 × 1014 gc/kg. Histologic and magnetic resonance imaging examinations revealed marked and sustained suppression of dystrophic pathology in all RGX-202-treated mice. Functionally, gains were observed in the in vitro specific force of extensor digitorum longus muscle, in vivo grip strength, and the rescue of treadmill and gait deficits. These findings provide preclinical evidence for the therapeutic efficacy of RGX-202 at a minimum effective dose (MED) of 1 × 1014 gc/kg in the murine DMD model. This MED served as the starting dose for the RGX-202 clinical study (NCT05693142), which has currently completed phase III enrollment.