Study Rationale: Parkinson’s disease (PD) is caused by the loss of neurons in the brain due to their inability to remove damaged and dysfunctional mitochondria. PINK1 kinase located on mitochondria is critical for the removal of damaged mitochondria. Mutations that decrease the activity of PINK1 are associated with PD. Progenra has developed highly potent and specific small molecule activators of PINK1 that enhance PINK1 activity in cells thereby promoting mitochondrial health. Our ultimate goal is to study the therapeutic effect of PINK1 activator drug candidates in treating PD in pre-clinical models.
Hypothesis: The current study aims to establish the differential activity of Progenra’s PINK1 activator(s) compared to the published PINK1 activator MTK-458. Subsequently we will evaluate the feasibility of PINK1 activator drugs to improve the clearance of damaged mitochondria and benefit patients with Parkinson’s Disease.
Study Design: The study is designed to evaluate the differential effectiveness of our PINK1 activator drugs in comparison to MTK-458 in biochemical as well as human and mouse cell models. We will also evaluate the effect of compounds on PINK1 variants. The efficacy and potential mechanism of action will be demonstrated. The differential effectiveness of the compounds will be determined by analyzing specific biomarkers such as pSer65Ub.
Impact on Diagnosis/Treatment of Parkinson’s disease: Current treatments for Parkinson’s disease have serious side effects and cannot prevent the destruction of neurons and do not treat the underlying causes of neurodegeneration. A successful PINK1 activator drug that efficiently removes damaged mitochondria may prevent neuronal loss and progression of Parkinson’s disease. Such a therapy can fundamentally change the way PD is treated.
Next Steps for Development: Once the proposed studies are successfully completed, we plan to conduct more pre-clinical drug efficacy and toxicity studies necessary to advance the drug candidate to clinical studies. This requires long-term safety studies, drug manufacturing and clinical trials.