Branka Grubor, Kate L. Henry, Su Jing Chan, Mark Sheehan, Anumeha Shah, Alex Pellerin, Judy Bai, Prasad Nadella, Santhosh Bommegowda, Patrick Cullen, Eric Tien, Vivian Chih-Wei Chen, Nicholas P. van der Munnik, Stephanie J. White-Hunt, Edward D. Plowey, Stefan Hamann, Amanda J. Guise, Shanqin Xu, Melissa Kirkland, Jessica Doherty, Eugenia Lyashenko, G. Jayarama Bhat, Kelly E. Glajch, Shih‐Ching Lo, Davide Gianni, Pete Clarner, Jake Gagnon, Jenhwa Chu, Kalyani Nambiar, Mukesh Lulla, Fengmei Zheng, Asmerom Weldeab, Dan Bartlett, Amos Gutnick, Taylor L. Reynolds, Kan Zhu, Dann Huh, Thomas M. Carlile, James Fikes, Patrick Trapa, Junghae Suh, Dale L. Morris, Linda C. Burkly
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.