289th ENMC international workshop: assessing and managing emerging AAV related toxicities after gene therapy for neuromuscular disorders, 26 - 28 September 2025, Hoofddorp, The Netherlands.
Adeno-associated virus (AAV) mediated gene therapies has emerged as a potentially transformative treatment approaches for neuromuscular disorders, with two FDA-approved products now in widespread clinical use: onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne Muscular Dystrophy. However, severe and occasionally fatal adverse events affecting vital organs, including the blood, liver, muscle, and heart, have emerged in both clinical trials and real-world post marketing settings. The 289th European NeuroMuscular Centre (ENMC) workshop convened 38 participants from patient advocacy groups, industry, and preclinical and clinical research groups to collaboratively review these toxicities, their underlying mechanisms, and potential mitigation and monitoring strategies. Discussions addressed the clinical spectrum and biological drivers of these events, the respective roles of innate and adaptive immunity, the contribution of specific vector characteristics as well as of the specific disease and recipient. The application of risk stratification and immunosuppressive regimens for prevention, monitoring, and management were considered. Emerging toxicities, including capillary leak syndrome, endothelial and dorsal root ganglia injuries, were reviewed alongside corresponding preclinical data from non-human primates. Participants agreed on the need to harmonize standard operating procedures, clinical guidelines, and data-sharing practices, and endorsed collaborative initiatives to proactively address critical gaps and unresolved key questions through a patient-centered framework.