Feasibility and Safety of Systemic Raav9-Hnaglu Delivery for Treating Mucopolysaccharidosis IIIB: Toxicology, Biodistribution, and Immunological Assessments in Primates

No treatment is currently available for Mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosmal storage disease. In anticipation of a clinical gene therapy treatment for MPS IIIB in humans, we tested the rAAV9-CMV-hNAGLU vector administration in primates at 1E13vg/kg or 2E13vg/kg via intravenous injection. There were no adverse events or detectable toxicity over a 6mo period. Gene delivery resulted in persistent global CNS and broad somatic transduction, with NAGLU activity detected at 2.9 to 12- fold above endogenous levels in somatic tissues and 1.3 to 3-fold above endogenous levels in the brain. Secreted rNAGLU was detected in serum. Low levels of pre-existing anti-AAV9 antibodies did not diminish vector transduction. Importantly, high level pre-existing anti-AAV9 vector lead to reduced transduction of liver and other somatic tissues, but had no detectable impact on transgene expression in the brain. ELISA showed antibody responses to both AAV9 and rNAGLU in treated animals. Serum anti-hNAGLU antibodies, but not anti-AAV9 antibodies, correlated with the loss of circulating rNAGLU enzyme. However, serum antibodies did not affect tissue rNAGLU activity levels. Weekly or monthly peripheral blood INFƳ-ELISPOT assays detected a CD4+ T-cell (Th-1) response to rNAGLU only at 4wk pi in one treated subject, without observable correlation to tissue transduction levels. The treatment did not result in detectable CTL responses to either AAV9 or rNAGLU. Our data demonstrate an effective and safe profile for systemic rAAV9-hNAGLU vector delivery in primates, supporting its clinical potential.