Abstract Body (Do not enter title and authors here): Introduction: Although adeno-associated (AAV) gene-replacement therapy is a potential transformative therapy for severe genetic diseases, their cardiac-immunotoxicity may pose challenges to broad clinical adoption. The pooled incidence and clinical significance of immune-mediated myocarditis in this setting is unknown.
Methods: MEDLINE, Embase, Pubmed were searched for studies of patients treated with AAV-replacement therapy. Type of vector used, dose, immunosuppressive regimen, clinical significance of the adverse event (AE) were extracted by 2 reviewers. Random-effects models were fitted using restricted maximum likelihood estimation and the method of Hartung, Knapp, Sidik, and Jonkman. VigiBase was searched for the occurrence of myocarditis with commercially available gene replacement drugs.
Results: 80 studies including 1939 patients were analyzed. A total of 734 AE were identified over 2122 patients-years of pooled-observation. 71 cases of myocarditis were reported, with 1 treatment-related death. Pooled incidence and rate per 100 patient-years were: 6.2%[95%CI:4.6%-8.1%;I²=46%], 8.6%[95%CI: 5.8%-10.7%;I²=63.2%]. 36(51%) patients experienced concomitant hepatitis. Events occurred in patients with Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, X-Linked Myotubular Myopathy, with rAAVs, AAV-8,9. All patients received a dose>10⁽¹³⁾vg/kg. Myocarditis peaked at week-2 after therapy, with no cases >month-1 post-injection. Most myocarditis did not have a relevant clinical impact (68,94%): only 4(6%) cases had decreased ejection fraction and wall motion abnormalities. The latters, recovered during the follow-up. The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction. Myocarditis was probably part of the clinical picture, but did not represent the direct cause of death. In VigiBase, myocarditis occurred in relation to Delandistrogene Moxeparvovec (1/16(6%)) and Onasemnogene Abeparvovec (14/217 (6%)).
Conclusions: Six percent of patients treated with AAV gene therapy experienced immune mediated myocarditis, most of which were early onset and clinically mild. One death occurred in the settings of a capillary leak-syndrome and cardiac dysfunction. These findings underscore the relative rarity of clinically significant cardiac sequale. Vigilant early cardiac monitoring, particularly within the first month of administration, in patients treated with AAV-8,9 and rAAVs at doses>10⁽¹³⁾vg/kg should be adopted.