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.

BACKGROUND: 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. OBJECTIVE: To systematically evaluate and quantitatively synthesise clinical evidence on the efficacy and safety of AAV-based gene therapies in DMD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. PROSPERO REGISTRATION NUMBER: CRD420261293429.