AAV5-GBA1

Delivering drugs effectively to the central nervous system (CNS) is a major challenge in drug development, including adeno-associated virus (AAV) gene therapy. The cerebrospinal fluid (CSF) circulates through the ventricular system and the subarachnoid space, surrounding both the brain and spinal cord, making it an attractive target for CNS drug delivery. Here, we compare intra-cisterna magna (ICM) administration of four AAV serotypes, AAV1, AAV5, AAV9, and AAVDJ, carrying glucosylceramidase beta 1 (GBA1) cDNA encoding the lysosomal enzyme β-glucocerebrosidase (GCase), in non-human primates (NHPs). Mutations in GBA1 are causative for Gaucher's disease (GD) and the most important genetic risk factor for Parkinson's disease (PD). AAV delivery of GBA1 is a promising therapeutic approach for GD and PD, assuming effective delivery to the target tissues. Our data show no significant difference in biodistribution among AAV serotypes. ICM administration effectively delivers GCase to the spinal cord and dorsal root ganglia, though distribution to deep brain regions is limited. The ICM procedure was well tolerated with no significant toxicity. To improve delivery to deep brain regions, AAVs with blood-brain barrier (BBB)-penetrating capabilities, protein-engineered GCase enzymes optimized for secretion and cross-correction, or delivery methods such as convection-enhanced delivery or ultrasound-focused technology may be required.