Study Rationale: In people with Parkinson’s disease (PD), neurons exhibit decreased ability to remove cellular trash. This dysfunction is caused by a reduction in the number and effectiveness of the cell’s trash cans, or lysosomes, and a decline in the delivery of cellular debris to these receptacles, a process called macroautophagy. Activation of TRPML1, a channel that resides on the lysosome, has been shown to boost macroautophagy and increase lysosome function and number in cells. Developing small molecules that can activate TRPML1 could produce a treatment that would alleviate symptoms and slow disease progression in people with PD.
Hypothesis: We hypothesize that small molecules that can activate TRPML1 should increase macroautophagy and enhance lysosome function in animals and potentially in humans.
Study Design: In this grant, we seek to identify additional, accessible biomarkers to confirm that our TRPML1 activators are working effectively in the brains of those treated with the therapeutic. We will also conduct animal safety studies on our compounds. If these studies they do not show major adverse findings at doses required to produce a therapeutic effect, we will be prepared to submit an application for approval to conduct clinical trials in humans.
Impact on Diagnosis/Treatment of Parkinson’s disease: Success in developing biomarkers for brain activity will allow us to confirm that our compounds can be given safely at doses predicted to be therapeutically beneficial and would provide a strong body of evidence that supports the development of small molecule, TRPML1 activators for the treatment of PD.
Next Steps for Development: Success in this grant would provide strong support for the continued advancement of Libra’s small compound TRPML1 activators into safety and clinical proof-of-concept studies in the clinic.