Study Rationale: While the cause of Parkinson's disease (PD) remains unknown for most patients, strong evidence indicates that damaged mitochondria in neurons likely play a causal role. Mitochondria are the “powerhouses” of cells, providing the energy needed for cellular function. Like any powerplant, damaged mitochondria can emit toxic materials, triggering inflammation and immune responses. A process called mitophagy removes these damaged mitochondria, allowing cells to replace them with healthy ones. Disruption of mitophagy in individuals with specific genetic mutations causes familial forms of PD. In idiopathic PD, mitophagy is also impaired, leading to the accumulation of dysfunctional mitochondria and progressive brain cell damage. Our approach centers around using an oral small molecule that can increase mitophagy in the brain in preclinical models by reducing the activity of an enzyme called USP30. Enhancing mitophagy has the potential to stop progressive degeneration and become the first ‘disease modifying’ therapy for PD.
Hypothesis: We hypothesize that Vincere’s molecule that reduces USP30 activity and enhances mitophagy will be shown to meet FDA guidelines for safety, enabling advancement to human clinical trials.
Study Design: We will conduct a series of studies to determine whether Vincere’s molecule can be safely administered to animals at high doses. We will assess the animals’ tolerance to different dose levels, measure drug levels in their blood, and evaluate potential effects on organs. These findings will guide dosing for future clinical trials in PD patients. Simultaneously, we will develop biomarkers, such as blood tests, to help evaluate how the molecule affects cellular processes related to mitophagy and Parkinson’s disease in humans.
Impact on Diagnosis/Treatment of Parkinson’s disease: Currently, no treatment halts the progression of PD. Vincere’s molecule has the potential to be the first therapy that slows disease progression rather than just masking symptoms. These FDA-required safety studies are a critical step toward testing the molecule in patients.
Next Steps for Development: If successful, this work will support an Investigational New Drug (IND) application to the FDA. Upon review, the agency will determine whether the molecule can proceed to a first-in-human study in healthy volunteers, followed by testing in PD patients.