Study Rationale: Mitochondrial dysfunction is extensively associated with genetic and sporadic forms of Parkinson’s disease (PD). Yet there are currently no clinical trials that specifically aim to enhance mitophagy — the selective removal of damaged or superfluous mitochondria — as a therapeutic strategy. Vincere has developed potent and selective inhibitors of USP30, an enzyme that marks mitochondria for destruction. These inhibitors enhance mitophagy in isolated human neurons. Here we aim to determine whether these small molecules can successfully enhance mitophagy under normal, baseline conditions and following induced mitochondrial damage in the brains of rodents.
Hypothesis: We hypothesize that USP30 inhibitors can enhance mitophagy in the brains of rodents, an effect we predict will be enhanced following mitochondrial damage.
Study Design: In this collaborative study, we bring together the expertise of three stellar groups in industry and academia to test the effect of USP30 inhibition in three transgenic mouse lines and in rat brains under basal conditions and after exposure to mitochondrial insult. The studies validate the ability of the inhibitor to interact with USP30 in the brain, and they will demonstrate the effect of USP30 inhibition on neurodegeneration with relevance to PD. Combined with data derived from treatment of cells from people with PD, these studies should reveal the inhibitors’ potential efficacy.
Impact on Diagnosis/Treatment of Parkinson’s disease: The small molecules proposed herein directly have the potential to modify disease progression in genetic and sporadic forms of PD.
Next Steps for Development: Vincere is performing efficacy (in human induced pluripotent stem cells), biomarker, and IND-enabling studies to advance these small molecules to the clinic.