Study Rationale: Impaired function of cell structures called mitochondria plays a key role in the pathology of Parkinson’s disease (PD): alpha-synuclein accumulation damages mitochondria, dopamine-producing neurons are sensitive to toxins generated by mitochondria and genes involved in mitochondrial quality control, such as Parkin, cause early-onset PD. The Reduced Parkin activity is thought to lead to accumulation of damaged mitochondria, reduced cellular energy production and increased generation of mitochondrial toxins, leading to the loss of dopamine-producing neurons. Our goal is to develop a drug candidate that increases Parkin activation to increase mitochondrial health and protect dopamine neurons in people with PD.
Hypothesis: The death of dopamine-producing neurons is driven, in large part, by diminished clearance of defective mitochondria due to reduced Parkin activity or alpha-synuclein aggregation. We hypothesize that increasing Parkin activity will restore the function of dopamine neurons in people with PD.
Study Design: We have identified small molecules that increase Parkin activation by enhancing Parkin recruitment specifically to damaged mitochondria, thereby facilitating their clearance. Our plan is to structurally modify these small molecules to improve their activity and drug-like properties using medicinal and computational chemistry approaches with a goal of achieving Parkin activation and protection of dopamine-producing neurons in the brain. Novel biomarkers will be used to track Parkin activation and mitochondrial turnover both in cells and in preclinical models of PD. We will also assess whether our compounds rescue impairments in cellular and preclinical PD models.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our approach has the potential to produce a first-in-class, disease-modifying therapeutic for individuals with sporadic PD that will repair the underlying mitochondrial defects as a stand-alone treatment or in combination with existing therapies.
Next Steps for Development: The main goal of this project is to select a candidate therapeutic molecule that will enter preclinical development to measure target engagement, safety and tolerability in animal studies. If successful, we will apply for FDA authorization to proceed with clinical studies in people with PD.