Study Rationale: Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated alpha-synuclein inside neurons in the brain. This may either arise from, or be exacerbated by, disrupted function of the lysosome, which is involved in the breakdown, removal, and recycling of cellular garbage. Activation of TRPML1, a lysosomal membrane calcium ion channel, has been shown to restore lysosomal function and help clear the harmful aggregates in various cellular models.
Hypothesis: We hypothesize that activation of TRPML1 by a novel, small molecule modulator will increase the number of lysosomes and improve their overall functional capacity to clear harmful alpha synuclein protein aggregates in neuronal cells, therefore improving overall brain health.
Study Design: We have made potent and highly brain penetrable small molecules that can selectively activate TRPML1 channels, and early pilot data shows promise in animal models of PD. We now want to confirm its therapeutic potential in Parkinson’s disease mice and to develop a robust biomarkers of the molecule’s therapeutic action in the blood, so that we can translate these findings into human testing.
Impact on Diagnosis/Treatment of Parkinson’s disease: The successful demonstration of enhanced lysosomal function, removal of alpha-synuclein protein aggregates and improvements in brain health and motor function will be a promising indicator for a potential first-in-class disease-modifying treatment for PD patients in the future.
Next Steps for Development:Once we demonstrate efficacy and target engagement in mice, and establish the proper dose range for future studies, we will then proceed to conduct comprehensive safety pharmacology and toxicology studies to support filing an application with the FDA for the initiation of phase I clinical trials in humans.