Study Rationale: Lysosomal dysfunction impairs cells’ ability to recycle their damaged components and is a primary contributor to the progression of Parkinson's disease (PD). TMEM175, a novel ion channel localized on lysosomes, acts as a reliable genetic signal for PD risk. While one variant leads to reduced channel activity, impaired lysosomal function and earlier disease onset, while a second, protective variant increases the channel’s activity and bolsters lysosomal health. These findings suggest that activating TMEM175 could be a promising therapeutic approach for PD. We are advancing small molecule TMEM175 agonists and developing translational biomarkers to push this program towards clinic.
Hypothesis: We hypothesize that enhancing TMEM175 activity in the brain using a small molecule agonist could improve lysosomal function and slow PD progression.
Study Design: Our team has identified several brain-penetrating lead chemicals with diverse structures. We will optimize the lead compounds using structures obtained through cryo-electron microscopy to accelerate their development towards clinical candidates. Meanwhile, we will conduct studies to identify novel translational biomarkers, which will strengthen our therapeutic hypothesis, and to identify the appropriate patient population and enable the measurement of target modulation in clinical studies.
Impact on Diagnosis/Treatment of Parkinson’s disease: Current therapeutics for PD address symptoms and do not treat the underlying causes of the disease. Driven by compelling genetics and biology, we aim to address the root causes of PD by advancing TMEM175 small molecule agonists to enhance lysosomal functions and slow disease progression.
Next Steps for Development: We will assess our translational biomarkers in samples from healthy volunteers and people with PD to evaluate their clinical feasibility and use them to identify a PD population with impaired TMEM175 function. We will perform toxicology studies on our lead compound in preparation for potential IND/CTA filing and clinical trials.