Incidence, Timing and Clinical Significance of Immune-Mediated Myocardial Injury and Myocarditis After Gene Replacement Therapy: A Systematic Review and Meta-Analysis

BACKGROUND: Although adeno-associated virus (AAV) gene-replacement therapy is a potentially transformative therapy for severe genetic diseases, its cardiac immunotoxicity may challenge broad clinical use. METHODS: Medical Literature Analysis and Retrieval System Online, Embase, and PubMed databases were searched from January 2005 to March 2025. Studies including patients treated with AAV-replacement therapy were deemed eligible. Prespecified items (type of vector, dose, timing, and clinical significance of the adverse event) were extracted by 2 independent observers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman (International Prospective Register of Systematic Reviews [PROSPERO]. VigiBase and the US Food and Drug Administration Adverse Event Reporting System were searched for the occurrence of myocarditis with commercially available AAV-replacement drugs. RESULTS: Eighty studies including 1939 human patients were analyzed. A total of 734 adverse events were reported over 2122 patient-years of pooled observation. Seventy-one cases of myocarditis were identified. The pooled incidence rate per 100 patient-years was 8.6 (95% CI, 5.8-10.7; I2=63.2%). Events occurred in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and X-linked myotubular myopathy, with recombinant AAVs and adeno-associated virus serotype 8. All received an intravenous dose >1013 vector genomes per kilogram body weight. Myocardial injury peaked in week 1 after injection (90% [95% CI, 85.7%-96.2%]; I2=43.2%), whereas myocarditis occurred mostly after week 2 (55% [95% CI, 48.7%-65.2%]; I2=33.1%), with no cases after the first month. Most myocarditis/myocardial injury did not have a relevant clinical impact (62, 87%), with only 8 (12%) cases having transient left ventricular dysfunction. The latter recovered during the follow-up. The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction. Myocarditis occurred in relation to delandistrogene moxeparvovec (1/16 [6%]) and onasemnogene abeparvovec (14/217 [6%]) in the Food and Drug Administration Adverse Event Reporting System and VigiBase. CONCLUSIONS: Immune-mediated myocarditis/myocardial injury after systemic AAV gene therapy occurred in <10 per 100 patient-years (peaking at weeks 1-3) and was usually clinically mild, with a minority showing transient dysfunction. All events followed intravenous doses >1×1013 vector genomes per kilogram body weight, clustered in neuromuscular programs, and were associated with certain recombinant capsids/serotypes. These data support intensive early cardiac monitoring, cautious dose selection, and delivery strategies to minimize systemic exposure. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251046546).