Study Rationale: A major problem in Parkinson’s disease (PD) is the buildup of a protein called alpha-synuclein, which damages brain cells. One way to help clear this toxic protein is by activating a natural cell-cleaning system called autophagy. Drugs that activate autophagy by blocking a protein called mTOR have shown promise in lab models—but these drugs also cause serious side effects in the periphery of the patient's body. This has limited their ability to be used to treat PD patients.
Hypothesis: We believe that we can safely activate autophagy in the brain without causing problems in the rest of the body. Our approach combines existing clinically-utilized mTOR-inhibiting drugs with a new compound that prevents these drugs from acting outside the brain. This “BrainOnly” strategy could help remove alpha-synuclein and protect brain cells while avoiding harmful side effects.
Study Design: We will test several FDA-approved mTOR inhibitors in combination with our peripheral blocker molecule. First, we will use lab-grown brain cells and Parkinson’s Disease mouse models to see which combination best clears aggregated alpha-synuclein. We’ll track key markers in the brain, blood, and spinal fluid to confirm that the mTOR inhibitors are working only in the brain. Promising drug combinations will then be tested in animal safety studies, with the goal of identifying a Development Candidate for advancement.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If successful, this project could deliver a first-of-its-kind treatment that safely boosts autophagy only in the brain. By clearing harmful proteins without the usual side effects of mTOR inhibitors, this approach may slow or stop PD progression. It could also help other diseases caused by protein buildup in the brain.
Next Steps for Development: Once the best drug combo is identified, we will perform safety studies and prepare for clinical trial testing, starting with testing in healthy volunteers and then people with PD.