Background:
Duchenne muscular dystrophy (DMD) is a severe X-linked disorder caused by mutations in the DMD gene, leading to the absence of dystrophin. Gene therapy, including exon skipping and adeno-associated viral (AAV) vector-mediated gene transfer, has emerged as a transformative approach to restore dystrophin expression and improve functional outcomes. However, questions remain regarding their efficacy and safety.
Objectives:
This systematic review evaluates the efficacy and safety of gene therapy in DMD, focusing on dystrophin restoration, functional improvements, and adverse events, while identifying factors influencing therapeutic outcomes.
Methods:
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov identified eligible clinical trials published up to 2024. Included studies assessed gene therapy interventions in DMD through dystrophin restoration or functional outcomes. Data were synthesized following PRISMA guidelines, and study quality was evaluated using the Cochrane Risk of Bias 2.0 tool.
Results:
Eighteen trials with over 1,200 participants demonstrated that AAV-based gene therapy increased dystrophin expression to 25%–40% of normal levels. Functional improvements included a mean increase of 35 meters in the 6-minute walk test (95% CI: 20–50; p < 0.001) and 3.2 points in the North Star Ambulatory Assessment (95% CI: 2.1–4.3; p < 0.01). Exon skipping therapies targeting exons 44, 45, and 51 effectively produced truncated but functional dystrophin. Adverse events, including mild immune responses and hepatotoxicity, were observed in 10%–15% of cases but were manageable. Subgroup analyses highlighted better outcomes with early intervention and optimized dosing.
Conclusion:
Gene therapy shows promise for DMD, achieving meaningful dystrophin restoration and functional improvements. Despite manageable safety concerns, further research is needed to confirm long-term efficacy and rare adverse effects. Personalized approaches, considering genetic mutations and disease stage, are critical for optimizing outcomes in this rapidly evolving field.