Adeno-Associated Virus Gene Therapy for Spinal Muscular Atrophy Induces Hepatotoxicity via Cytokine and Macrophage Activation.

Authors

Aiko Sakai, Masaya Sugiyama, Masafumi Onodera, Fujiko Fukushima, Mai Tanaka, Toru Uchiyama, Masashi Mizokami, Ryo Sumazaki

Published in

Liver international : official journal of the International Association for the Study of the Liver. Volume 46. Issue 8. Pages e70760.

Abstract

Hepatotoxicity is a common and significant adverse effect associated with adeno-associated virus (AAV) gene therapy; however, the underlying mechanisms remain unknown. In this study, we demonstrated innate immune activation in two patients with spinal muscular atrophy shortly after receiving AAV9 gene therapy with onasemnogene abeparvovec. Both patients developed marked hyperferritinemia accompanied by hepatotoxicity, thrombocytopenia, hypertriglyceridemia, and hypofibrinogenemia, all of which are the diagnostic criteria for macrophage activation syndrome. To evaluate their immune responses, serial analyses of serum cytokines/chemokines and flow cytometry were performed. Surges in macrophage-associated cytokine levels were observed in proportion to the severity of adverse events within 1 week after AAV vector infusion, suggesting that macrophage activation contributed to the pathogenesis of these adverse effects. Our findings clarify the immunological basis underlying hepatotoxicity in patients after AAV gene therapy. Furthermore, these findings provide a rationale for using various immunosuppressants or chemokine blockers in patients exhibiting severe adverse effects.

PMID:
42400303
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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