Inhibition of immune response reduces pathology in dorsal root ganglia and peripheral nerves in cynomolgus macaques following AAV gene therapy.

Administration of adeno-associated virus (AAV) gene therapies via blood or cerebrospinal fluid (CSF) in non-human primates (NHPs) can lead to degeneration of dorsal root ganglion (DRG) neurons and nerve fibers in the spinal cord and peripheral nerves. AAV cargo expression is implicated in AAV DRG toxicity, but the underlying mechanism(s) is unknown. Here, we performed a time course study of intra-cisterna magna (ICM) administration of an AAV9 variant encoding human survival of motor neuron 1 (hSMN1) to identify molecular and cellular changes preceding pathology. Increases in inflammatory gene modules, cerebrospinal fluid (CSF) cytokines, and immune cell infiltrates as early as day 5 prior to neuron and nerve fiber degeneration on days 15 and 29 suggested a role for the immune response in AAV-mediated toxicity. Prophylactic treatment with a glucocorticoid steroid dexamethasone and a calcineurin inhibitor tacrolimus diminished pathology in NHPs following administration of three AAV gene therapy vectors. Collectively, these data demonstrate a causal role for the immune response to AAV in AAV-mediated DRG and nerve fiber toxicity. The efficacy of immunosuppression with three different AAV cargos suggests broad utility across AAV vectors and provides a clinically feasible approach to mitigating this potential toxicity in patients.