Background
Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by mutations in the DMD gene, leading to loss of dystrophin protein. Gene editing techniques such as CRISPR-Cas9, base editing, and prime editing offer promising therapeutic approaches. These techniques differ in efficiency, precision, and safety. This systematic review and meta-analysis compare their effectiveness in dystrophin restoration, functional outcomes, and safety.
Objectives
To evaluate the effectiveness and safety of CRISPR-Cas9, base editing, and prime editing in restoring dystrophin expression, improving motor function, and minimizing off-target effects in DMD.
Methods
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov identified relevant studies published up to 2024. Eligible studies included RCTs, non-randomized trials, and preclinical research. Data were extracted following PRISMA guidelines, with risk of bias assessed using appropriate tools. A random-effects model was applied for meta-analyses.
Results
Twenty-eight studies involving 1,975 participants and animal models were included. CRISPR-Cas9 showed the highest dystrophin restoration (32.8%, 95% CI: 25.6–40.1%, p < 0.001), followed by base editing (24.5%, 95% CI: 18.7–30.3%, p < 0.001) and prime editing (20.1%, 95% CI: 15.4–24.8%, p < 0.001). Functional improvements in grip strength were greatest with CRISPR-Cas9 (3.4 points, 95% CI: 2.7–4.1, p < 0.001), compared to base editing (2.6 points) and prime editing (2.1 points). However, CRISPR-Cas9 had the highest off-target effects (OR: 1.85, 95% CI: 1.45–2.37, p < 0.001), while base editing (OR: 1.32) and prime editing (OR: 1.11) had better safety profiles.
Conclusion
CRISPR-Cas9 offers superior dystrophin restoration and functional improvement but with higher off-target risks. Base editing balances efficacy and safety, while prime editing provides precise editing with minimal off-target effects. These findings highlight the need for personalized approaches and further research to optimize safety and long-term outcomes in clinical settings.