Determinants of hepatic enzyme elevations following onasemnogene abeparvovec: Results from a unified immunomodulation protocol

IntroductionOnasemnogene abeparvovec is an adeno-associated virus serotype 9 (AAV9) gene therapy for spinal muscular atrophy (SMA) that is frequently associated with immune-mediated hepatotoxicity. Previous studies have suggested that older age and higher body weight may increase the risk or severity of hepatic enzyme elevation; however, interpretation is limited by heterogeneous immunosuppression strategies across centers.MethodWe conducted a retrospective cohort study of children with SMA who received onasemnogene abeparvovec between 2020 and 2025 and were managed using a unified, protocol-driven immunomodulation strategy. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values (upper limit of normal [ULN] 35 U/L), as well as the timing of peak transaminase elevations, were analyzed in relation to age and weight at infusion.ResultsAmong 152 children with adequate biochemical follow-up, hepatic enzyme elevation was common: 63.2% had peak ALT ≥2× ULN and 29.6% had peak ALT ≥5× ULN. Weight demonstrated a statistically significant but modest correlation with peak ALT magnitude (r = 0.184, p = 0.023), whereas age was not associated with transaminase severity. In contrast, age correlated with delayed timing of peak ALT (r = 0.229, p = 0.005) and AST (r = 0.283, p < 0.001). All hepatic enzyme abnormalities resolved under protocol-based immunomodulation, and no cases of hepatic failure or synthetic dysfunction occurred.ConclusionWhen managed with a structured, proactive immunomodulation protocol, hepatotoxicity following onasemnogene abeparvovec is predictable and manageable. Weight modestly influences ALT severity, while age primarily affects the timing rather than the magnitude of hepatic immune activation, supporting safe administration across a broad pediatric age and weight spectrum.