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).