Objective: Development of a gene therapy-based drug for treatment of GBA-PD, a genetic subtype of Parkinson’s disease

Background: Mutations in GBA1, the gene encoding glucocerebrosidase (GCase), are one of the most prevalent risk factors for Parkinson’s Disease (PD). GBA-PD patients form a genetically well-defined subpopulation within PD, characterized by heterozygous mutations in their GBA1 gene. The lysosomal enzyme GCase plays a pivotal role in catalyzing the hydrolysis of glycolipids, specifically glucosylceramide (GL1) and glucosylsphingosphine (Lyso-GL1). The reduction or loss of GCase activity leads to the accumulation of these substrates, thereby disrupting lipid homeostasis. In GBA-PD, this disruption further manifests as the accumulation of Lewy bodies containing α-synuclein, ultimately promoting neuronal cell death.

Method: We propose a one-time intra-CSF administration of AAV-GBA1 for the treatment of GBA-PD. To achieve broad distribution of GBA1 throughout the brain, we engineered GBA1 to enhance its secretion, facilitating cross-correction. We administered the engineered GBA1 variants, packaged in AAV.GMU1, a capsid with broad brain distribution. We demonstrate efficacy of our therapeutic product in both mice and non-human primates (NHPs) by inhibiting GCase activity with CBE (conduritol ß-epoxide), a covalent inhibitor of GCase.

Results: We generated four engineered GBA1 variants and using in vitro studies revealed that the subcellular localization and enzymatic activity of the variants is comparable to WT GBA1. Histological assessments revealed robust secretion and cross-correction of all our GBA1 variants. Among the variants we tested, the SS3-GBA1 variant outperformed by effectively clearing substrate accumulation in brains of both mice and NHPs. Ongoing dose range finding and tolerability studies in mouse models and NHPs aim to establish well-tolerated minimally efficacious dose for clinical application.

Conclusion: In summary, our AAV-based treatment combining unique capsid with novel transgene is a best-in-class gene therapy treatment for GBA-PD patients.

Note: A similar abstract will be presented at the upcoming ASGCT meeting in May 2024.

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/aav-mediated-gene-therapy-for-gba-pd/