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], REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251046546). 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: =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: 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.