Safety and efficacy of AAV-based mini- and micro-dystrophin gene therapies in Duchenne muscular dystrophy: a systematic review and meta-analysis of clinical trials.

Abstract

Adeno-associated virus (AAV)-mediated mini- and micro-dystrophin gene therapies have emerged as promising treatments for Duchenne muscular dystrophy (DMD), yet their overall efficacy and safety remain uncertain. To systematically evaluate and quantitatively synthesise clinical evidence on the efficacy and safety of AAV-based gene therapies in DMD. A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Five databases were searched from inception to November 2025. Clinical trials reporting functional and/or safety outcomes were included. Random-effects meta-analyses were performed for comparable outcomes. The study protocol was prospectively registered on PROSPERO. Nine studies (six trials; n=218) were included, with four contributing to the meta-analysis. Delandistrogene moxeparvovec improved North Star Ambulatory Assessment (NSAA) scores by +3.08 points at 1 year (95% CI 1.85 to 4.32), with greater effects in 4-5 year-olds (+4.06) than in 6-7 year-olds (+1.01). Improvements from baseline were observed in time to rise (-0.29 s) and four-stair climb (-0.48 s) but not in 10 or 100 m walk/run. Compared with controls, a significant effect was observed only for time to rise (-0.64 s), with no differences in NSAA or other timed tests. Effects were more consistent in younger patients. Fordadistrogene movaparvovec showed smaller effects. Most patients experienced treatment-related adverse events, mainly mild and transient; however, serious events, including hepatotoxicity and rare fatal outcomes, occurred. AAV-based gene therapies provide modest functional benefits in ambulatory boys with DMD, particularly at younger ages, but carry important safety risks. Larger trials with longer follow-up are needed to clarify long-term efficacy and optimise risk-benefit profiles. CRD420261293429.