Background:
Onasemnogene abeparvovec has transformed the therapeutic landscape of spinal muscular atrophy (SMA) but is frequently associated with immune-mediated hepatotoxicity. Early real-world cohorts suggested heavier or older children may exhibit more severe transaminitis, though findings were confounded by heterogeneous steroid practices. This study evaluated determinants of hepatic enzyme elevations in a large multinational cohort treated under a unified immunomodulation protocol.
Methods:
We conducted a retrospective observational study of 152 children with SMA who received onasemnogene abeparvovec (2020–2025) and had ≥5 weeks of ALT/AST monitoring. Weekly transaminases were analysed relative to a fixed upper limit of normal of 35 U/L. Outcomes included peak ALT/AST (severity), week of peak (timing), and immunosuppression requirements. All children were managed under a structured escalation protocol incorporating doubling prednisolone, adding intravenous methylprednisolone, and tacrolimus for steroid-refractory cases.
Results:
Transaminitis was common: 63.2% exceeded ALT >2×ULN, 48.7% exceeded >3×ULN, and 29.6% exceeded >5×ULN. Mean peak ALT was 5.49×ULN. Weight showed a modest but significant correlation with peak ALT (r=0.184, p=0.023), while age showed no association with peak ALT or AST. Peak AST did not correlate with either variable. In contrast, age was significantly associated with delayed peak timing for both ALT (r=0.229, p=0.005) and AST (r=0.283, p<0.001). Immunomodulation escalation was required in 42% (doubling prednisolone), 11% (intravenous methylprednisolone), and 7% (tacrolimus). No child developed hepatic failure or coagulopathy.
Conclusion:
In this large, ethnically diverse cohort, weight modestly influenced ALT severity, whereas age primarily determined the timing—but not the magnitude—of hepatic immune activation. A structured, escalation-based immunosuppression protocol effectively prevented clinically significant hepatotoxicity across the pediatric age and weight spectrum. The absence of synthetic dysfunction demonstrates that early, proactive immune-modulation prevents meaningful clinical hepatotoxicity. These findings challenge assumptions regarding weight-related risk and support harmonised, protocol-driven monitoring strategies for safe global delivery of AAV9 gene therapy.