Onasemnogene abeparvovec AAV9 gene therapy for SMA triggers hepatotoxicity via macrophage activation syndrome-like cytokine surges.

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by a deficiency in the SMN1 gene, leading to progressive muscle weakness and atrophy. Gene therapy using adeno-associated virus (AAV) vectors, such as onasemnogene abeparvovec, offers a promising therapeutic approach by delivering a functional SMN1 gene. However, a significant challenge with AAV gene therapy is the common occurrence of hepatotoxicity, whose underlying mechanisms are not fully understood. This adverse effect can limit treatment efficacy and patient safety, necessitating a clearer understanding of its immunological basis to develop targeted mitigation strategies.

Researchers investigated the immune responses in two patients with spinal muscular atrophy who developed adverse events shortly after receiving AAV9 gene therapy with onasemnogene abeparvovec. The study focused on characterizing the innate immune activation following the gene therapy. Serial analyses of serum cytokines/chemokines were performed to track inflammatory markers. Additionally, flow cytometry was utilized to evaluate immune cell populations and activation states. The primary endpoint was to identify the immunological basis contributing to the observed hepatotoxicity and other systemic adverse effects.

Both patients developed marked systemic adverse events, including hyperferritinemia, hepatotoxicity, thrombocytopenia, hypertriglyceridemia, and hypofibrinogenemia, which collectively meet the diagnostic criteria for macrophage activation syndrome (MAS). > Surges in macrophage-associated cytokine levels were observed in proportion to the severity of these adverse events within 1 week after AAV vector infusion. These findings strongly suggest that innate immune activation, specifically involving macrophages, significantly contributes to the pathogenesis of these severe side effects. The rapid onset of cytokine surges underscores the acute nature of this immune response, linking it directly to the AAV vector administration. This clarifies the immunological basis of hepatotoxicity and systemic inflammation post-AAV gene therapy.