Study Rationale: Autophagy is a process by which cells dispose of damaged or improperly functioning cell components. Recent evidence points at defects in autophagy as a feature of Parkinson’s disease (PD); impaired autophagy could allow the accumulation of alpha-synuclein aggregates in neurons, leading to neurodegeneration. Boosting autophagy reduces disease severity in preclinical animal models of PD and thus has potential as a treatment to modify PD progression. For this reason, we are developing small molecules that can enhance autophagy. Such novel compounds should reduce alpha-synuclein accumulation, improve motor function and slow the progression of disease.
Hypothesis: We aim to demonstrate that our compounds will reduce alpha-synuclein accumulation in the nervous system and improve motor and non-motor symptoms, effectively slowing down the progression of disease in a preclinical mouse model of PD.
Study Design: We will use transgenic mice that are able to produce the human alpha-synuclein protein in their nervous system; these animals exhibit motor and non-motor symptoms that are similar to those experienced by people with PD. We will treat these mice with our compound for two months and subsequently determine whether the treatment provided any health benefits. This assessment will be done via movement and behavioral tests as well as by measuring the levels of alpha-synuclein in the nervous system.
Impact on Diagnosis/Treatment of Parkinson’s disease: Currently available treatments for PD only address the symptoms but do not prevent the neuronal damage that occurs in the brain. Boosting autophagy early in the course of the disease holds the potential to protect neurons from harm and hopefully halt or delay the development of the disease.
Next Steps for Development: In parallel with this project, we are performing additional experiments in other cellular and preclinical models of PD; these include safety and toxicology studies in animals, which are a prerequisite to initiating clinical trials in humans. If successful, we hope to begin the first clinical trial in 2025.
Additional Support: The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity as a lead supporter providing funding for this project.