AAV gene therapy for GBA1-related diseases.

Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), are the most common risk factor for Parkinson's disease (PD). GBA-PD patients are a genetic subpopulation of PD carrying heterozygous mutations in GBA1. Additionally, bi-allelic mutations in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder. Loss of GCase activity, a lysosomal enzyme, leads to the accumulation of lipid substrates, disrupting lipid homeostasis and causing lysosomal dysfunction. Here, we report an AAV-mediated GBA1 replacement strategy to treat diseases arising from mutations in GBA1. We engineered human GCase to be readily secretable to facilitate broad cross-correction. We developed CBE (conduritol β-epoxide)-induced lipid accumulation models to assess efficacy in mice and non-human primates (NHPs). Based on data across species, we nominated AAV.GMU01 SS3-GBA1 as our lead candidate. SS3-GBA1 is robustly secreted, cross-corrects across tissues and promotes lipid clearance. By comparing human GCase levels in AAV-treated NHP brains to healthy human donor brains, we demonstrate that AAV.GMU01 SS3-GBA1 replenishes the GCase deficit seen in GBA-PD patients, thus restoring GCase to near-physiological levels. Importantly, AAV.GMU01 SS3-GBA1 is well tolerated with no adverse findings. Collectively, we establish a therapeutic strategy for the treatment of GD and GBA-associated PD with a single-gene therapy product.