Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial

Understanding how the immune system responds to adreno-associated virus (AAV) gene therapy and potentially modulating that response is vital to their safety and ultimate success. However, the immune response in the central nervous system (CNS) to AAV gene therapy is still not well understood. Here, we characterized the immune responses to AAVrh8 vectors injected into the thalamus and cerebral spinal fluid (CSF) of Tay-Sachs (TSD) and Sandhoff (SD) disease patients. Nine patients in four dose cohorts were treated with gene therapy while being immunosuppressed with rituximab, sirolimus and prednisolone. Neutralizing antibodies against AAV capsid were detected in the serum of 9/9 patients and in the CSF of 7/9 patients. Specific T-cell responses against the AAV capsid were documented in all patients, with most patients developing responses at 2–3 weeks post-injection. Flow cytometry suggested the induction of capsid-specific regulatory T-cells in the periphery. Local immune responses were detected by cytokine analysis of the CSF along with upregulation of several chemokines, including CXCL8, CXCL9 and CXCL10. These Phase I/II clinical trial data provide valuable insights into how the human immune system responds to direct administration of AAV into the CNS and important assessments on the efficacy of the immune suppression regimen which can be used to inform future AAV clinical trials.