Intra-CNS AAV9-GBA1 delivery yields species and route of administration differences in safety and transgene...

Adeno-associated virus (AAV) delivery of lysosomal enzymes to the brain is currently being tested in several clinical trials. However, publicly available non-human primate (NHP) studies comprehensively reporting biodistribution, transgene expression, and safety across the central nervous system (CNS) remain limited. Here, we examined AAV9-GBA1 (encoding glucocerebrosidase [GCase]) delivery to mice and NHPs. Loss-of-function GBA1 mutations cause Gaucher's disease and are risk factors for Parkinson's disease and dementia with Lewy bodies. In mice, early postnatal intracerebroventricular administration produced appreciable transgene expression and increased GCase activity in the brain without adverse findings. Two independent adult NHP studies evaluated AAV9-GBA1 brain delivery via intracisterna magna (ICM) and intraparenchymal (IPa) administration. ICM delivery produced considerable transgene expression in the spinal cord and dorsal root ganglia (DRG) neurons along with adverse microscopic findings, but limited brain expression and activity. In contrast, IPa delivery into the thalamus and/or putamen produced substantial transgene expression and GCase activity in injected and connected brain regions, with limited effects in distal regions, including the spinal cord. While no AAV-related DRG toxicity was detected with IPa, procedure- and AAV9-GBA1-related adverse microscopic brain findings were observed and associated with clinical outcomes. Further technological advances are needed to achieve safe and therapeutic AAV transgene expression in NHP brain.