Immune-mediated myocarditis after systemic AAV gene therapy occurred at a pooled incidence of 8.6 per 100 patient-years (95% CI, 5.8-10.7), mostly following intravenous doses >10^13 vg/kg.
Meta-Analysis (n=1,939)
Does adeno-associated virus (AAV) gene-replacement therapy cause immune-mediated myocardial injury and myocarditis in patients with severe genetic diseases?
High-dose intravenous AAV gene replacement therapy is associated with a clinically mild but notable risk of immune-mediated myocarditis (8.6 per 100 patient-years) peaking at 1-3 weeks, warranting intensive early cardiac monitoring.
Estimación del efecto: Incidence rate 8.6 (95% CI 5.8-10.7)
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: 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; I 2 =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 >10 13 vector genomes per kilogram body weight. Myocardial injury peaked in week 1 after injection (90% 95% CI, 85.7%–96.2%; I 2 =43.2%), whereas myocarditis occurred mostly after week 2 (55% 95% CI, 48.7%–65.2%; I 2 =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 1×10 1 3 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.
Maurizi et al. (Tue,) conducted a meta-analysis in Severe genetic diseases (Duchenne muscular dystrophy, spinal muscular atrophy, X-linked myotubular myopathy) (n=1,939). Adeno-associated virus (AAV) gene-replacement therapy was evaluated on Incidence of myocarditis per 100 patient-years (Incidence rate 8.6, 95% CI 5.8-10.7). Immune-mediated myocarditis after systemic AAV gene therapy occurred at a pooled incidence of 8.6 per 100 patient-years (95% CI, 5.8-10.7), mostly following intravenous doses >10^13 vg/kg.