Study Rationale: The most prevalent genetic risk factors for Parkinson’s Disease (PD) are mutations in GBA1, the gene that encodes the glucocerebrosidase (GCase) enzyme. Dysfunction of GCase leads to accumulation of lipids in the lysosomes as well as the formation of alpha-synuclein aggregates. Nature-identical human GCase is an ineffective and difficult to manufacture therapeutic and in this project, we will assess the efficacy of more stable and manufacturable versions of human GCase as a potential enzyme replacement therapy for PD.
Hypothesis: In this project, we aim to demonstrate that engineered, highly stable variants of human GCase hold promise as potential therapies for Parkinson's disease (PD), and that modulating GCase-protein interactions via specific enzyme variants can enhance therapeutic efficacy.
Study Design: We previously discovered GCase variants that when administered to the PD mouse model as gene therapy outperform human GCase pharmacodynamically. We will genetically fuse these stable GCase variants to a peptide that has been shown to be effective in aiding the transport of the enzyme across the blood-brain-barrier. These BBB-GCase sequences will be manufactured and tested in the D409V or 4L/PS-NA PD small pre-clinical model for a range of therapeutically relevant properties.
Impact on Diagnosis/Treatment of Parkinson’s disease: Lack of efficacy is a frequently cited reason for discontinuation of drug development programs. With the optimized versions of human GCase that we study in this project, we raise the potential for an enzyme replacement therapy to become an efficacious disease-modifying treatment for PD.
Next Steps for Development: Upon satisfactory outcome of this project, the next steps will include IND-enabling development of the lead candidate for subsequent clinical studies. In parallel, additional studies in cell lines, brain organoids, and small pre-clinical models, will assess the potential use of these GCase variants in idiopathic PD.