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Development of a Novel TRPML1 Activator for Parkinson’s Disease

Study Rationale:
A primary cause of Parkinson’s disease is build-up of a toxic protein in specific neurons in the brain. There is evidence that in Parkinson’s disease the cellular machinery to clear this protein build-up is impaired, and that activation of this cellular process, known as autophagy, in models can help remove the protein build-up and slow down disease progression. We will develop a new class of drugs that increase activity of this pathway through activation of TRPML1, a calcium channel in the cell.

We hypothesize that drugs targeting TRPML1 will be effective in slowing disease progression in Parkinson’s disease models. Increased activity of the TRPML1 calcium channel will promote autophagy, leading to clearance of protein build-up in specific brain neurons impacted by Parkinson’s.

Study Design:
The initial goal of the study is to develop a drug that can pass from the blood into the brain to activate the TRPML1 calcium channel. This will be achieved through additional chemistry to optimize the current drug candidates. The optimized drugs will then be tested in brain cell models of Parkinson’s disease. Finally, drugs shown to be effective in these cell models will be tested in an established pre-clinical model of Parkinson’s disease.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Current treatments for Parkinson’s disease do not address the build-up of toxic protein in the diseased neurons. Drugs that activate the autophagy pathway to clear the protein build-up represent an innovative approach for treatment of the disease, which could be used alone or in combination with existing therapies.

Next Steps for Development:
Drugs that successfully slow disease progression in Parkinson’s disease models will be further developed to obtain data to support filing of an investigational new drug with the U.S. Food and Drug Administration. This filing will enable initiation of a clinical trial in Parkinson’s disease patients to study the safety and effectiveness of the drug.


  • Daniel S. Ory, MD

    Cambridge, MA United States

  • Ellen Sidransky, MD

    Bethesda, MD United States

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