Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. The current study characterizes key aspects of AAV-induced hepatotoxicity in nonhuman primates, highlighting the usefulness of this nonclinical species for studying liver injury.
Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 adminis-tration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellu-lar necrosis and deteriorating clinical condition. These tran-sient acute liver injury marker elevations occur from 3-4 days post intravenous administration to = 2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal adminis-tration of empty capsids or a promoterless genome vector, suggesting that liver injury after cerebrospinal fluid dosing nonhuman primates is driven by viral transduction and trans-gene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the use-fulness of this nonclinical species in that context.
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