Background:
Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by mutations in the DMD gene, leading to dystrophin deficiency and severe muscle degeneration. Exon skipping strategies, utilizing antisense oligonucleotides (AONs), aim to restore the DMD reading frame by inducing targeted exon exclusion, enabling production of a truncated yet functional dystrophin protein. Although preclinical and clinical studies have demonstrated promising results, the variability in efficacy and safety across different approaches necessitates a comprehensive analysis.
Objectives:
This meta-analysis evaluates the efficacy and safety of exon skipping therapies in preclinical models and clinical trials of DMD. It aims to quantify dystrophin restoration, assess improvements in functional outcomes, and analyze safety profiles across various strategies, including exon 44, 45, and 51 skipping.
Methods:
A systematic search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov identified relevant preclinical and clinical studies published up to 2024. Eligible studies included those reporting dystrophin expression, functional improvements, or adverse events associated with exon skipping therapies. Data were synthesized using meta-analytical techniques, and study quality was assessed using appropriate risk of bias tools.
Results:
Analysis of 25 preclinical studies and 15 clinical trials (totaling over 1,500 subjects and animal models) showed that exon skipping therapies consistently increased dystrophin expression. In preclinical models, exon skipping restored dystrophin levels to an average of 30%–45% of normal, correlating with improved muscle strength (mean increase: 35%, 95% CI: 28%–42%, p < 0.001). In clinical trials, dystrophin restoration ranged from 5%–15% of normal levels, accompanied by significant improvements in 6-minute walk distance (mean increase: 25 meters; 95% CI: 15–35 meters, p < 0.01) and reduced disease progression. Adverse events were generally mild, including injection site reactions and transient creatine kinase elevations, with no severe safety concerns reported. Subgroup analyses revealed greater efficacy with early intervention and optimized dosing regimens.
Conclusion:
Exon skipping therapies represent a promising approach for DMD treatment, achieving meaningful dystrophin restoration and functional improvements while maintaining favorable safety profiles.