Funded Studies
Study Rationale: Mutations in GBA1, the gene that encodes glucocerebrosidase (GCase), diminish GCase activity in an estimated 7 to 10% of people with Parkinson’s disease (PD). In addition, reduced GCase activity has also been reported in cases of idiopathic PD (iPD). This loss of activity fuels the development of many PD-related phenomena, such as the accumulation of alpha-synuclein and glucosylsphingosine. This buildup disrupts the function of the lysosome, a recycling center that maintains overall cellular health. We plan to alleviate these disease-related molecular disturbances by restoring GCase activity using potent, small-molecule activators in neurons derived from patients’ induced pluripotent stem cells (iPSCs).
Hypothesis: We hypothesize that small-molecule GCase activators will be effective at reducing or preventing PD-related cellular phenomena in GBA1 mutant and iPD-derived neurons, thereby slowing, or halting the progression of PD in patients.
Study Design: We plan to generate long-term cultures of iPSC patient-derived neurons from a large and diverse cohort of iPSC lines from the Parkinson’s Progression Markers Initiative. Establishment of long-term neuronal cultures is necessary to allow the accumulation of both alpha-synuclein and glucosylsphingosine. We will then treat these neurons with potent GCase activators and assess the therapeutic benefit in cells derived from individuals with GBA1 mutations or iPD compared to those of healthy volunteers.
Impact on Diagnosis/Treatment of Parkinson’s disease: This study aims to answer several important questions: What level of GCase activation is needed to prevent or reverse PD-associated cellular phenomena and will GCase activation be beneficial for iPD patients? Overall, the results from this study will help to inform future dosing of GBA1-PD and iPD patients during clinical development of GCase activators.
Next Steps for Development:We aim to assess the efficacy of GCase activators in future GBA1-PD targeted clinical trials.