Title : Efficacy and safety of exon-skipping therapies in Duchenne muscular dystrophy: An updated systematic review and meta-analysis.
Abstract:
Introduction: Duchenne muscular dystrophy (DMD) is an X-linked progressive neuromuscular disorder resulting from mutations in the dystrophin gene, which cause membrane instability, myofibril degradation, cardiomyopathy, respiratory failure, and premature mortality. While corticosteroids and physiotherapy address only the symptoms, mutation-specific antisense oligonucleotide (ASO)-mediated exon skipping has been developed to restore the dystrophin reading frame and produce a partially functional dystrophin protein. Our study assessed the efficacy and safety of exon-skipping therapies in patients with DMD, focusing on randomized, double-blind RCTs or first-phase controlled crossover trials.
Methods: Comprehensive searches were conducted across databases, including PubMed, EMBASE, Scopus, CENTRAL, ClinicalTrials.gov, and additional registries, from inception until January 2026. Nine randomized controlled trials (RCTs) met the eligibility criteria for inclusion. The quality of the studies was assessed using the Cochrane Risk of Bias Tool 2 (ROB 2). RevMan 5.4 was used to pool risk ratios and mean differences using fixed- or random-effects models based on heterogeneity (I²). The effectiveness of antisense oligonucleotide treatment was measured using the clinically evaluated North Star Ambulatory Assessment (NSAA) score and the 6-minute walk test (6 MWT) score. Adverse outcomes associated with the DMD oligonucleotides were also assessed.
Results: Exon-skipping therapies demonstrated no significant difference compared to placebo in terms of overall adverse events (fixed-effects RR=1.00, 95% CI 0.94–1.07; random-effects RR=0.97, 0.78–1.21) or in the incidence of back pain, nasopharyngitis, or oropharyngeal pain. However, there was a notable increase in injection-site reactions (fixed-effects RR=4.49, 2.70–7.46; random-effects sensitivity RR=3.65, 1.79–7.43), and renal toxicity exhibited an elevated signal in sensitivity analyses (RR≈1.89–1.90), whereas extremity pain decreased (RR≈0.40–0.42). At the 24-week mark, functional efficacy was not conclusively improved: the change in NSAA was non-significant overall (fixed MD=−0.16; random MD=1.20; I²=82%), and the 6-minute walk distance did not show significant benefit (fixed MD=−12.45; random MD=−16.26; I²=63%), although NSAA subgroup effects favored eteplirsen
Conclusion: Our meta-analysis indicates that exon-skipping therapies are generally well tolerated; however, they necessitate monitoring for injection-site reactions and potential renal toxicity. Furthermore, clinically assessed functional outcomes, such as the North Star Ambulatory Assessment (NSAA) and 6-minute walk test (6 MWT) scores, showed no significant improvement, highlighting the need for rigorous studies. Future trials should incorporate refined endpoints, neonatal screening for earlier diagnosis, and the development of more sensitive biomarkers to monitor disease progression and therapeutic responses. Additionally, the inclusion of larger, diversified populations is essential, as exon-skipping therapies are mutation-specific and target particular exons. Enhanced delivery of antisense oligonucleotides (ASO) to target tissues using peptide conjugates or viral vectors, as well as the utilization of combination therapies, should be considered. The success of exon-skipping drugs can potentially minimize disease progression, improve or stabilize motor function, preserve the function of cardiac and respiratory muscles, and ultimately improve the prognosis and extend the lifespan.
