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Funded Studies

Chemical Modulator of Chaperone-mediated Autophagy in Parkinson's Disease

Brain cells depend on very efficient surveillance systems to identify defective components and break them apart to avoid accumulation and toxicity. We have found that in the brain cells of Parkinson's disease (PD) patients, one of these cleaning mechanisms malfunctions, contributing to cellular cluttering and toxicity. In this study we intend to develop drugs to enhance the activity of this cleaning system as a possible future treatment for PD. This is an ideal moment to conduct this research because of the rapid advances in the last five years on our understanding of cell surveillance mechanisms. We have obtained very promising results in cellular experimental system that have encouraged us to consider further developing these compounds for their possible use in clinic.

Project Description:
Our laboratories have recently developed the first prototype drugs capable to activate a specific cleaning mechanism inside cells. We propose that these drugs, after necessary modifications, could be utilized to eliminate the abnormal proteins that accumulate in the brain of PD patients. We intend to use medicinal chemistry to further develop these drugs to increase their potency, improve their delivery to the brain and reduce any possible side effect toxicity. The strength of the collaboration between our two groups is that it brings together expertise in medicinal chemistry and in neuroscience required to generate the new drugs and test their cellular and in vivo efficacy.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A drug that can enhance the activity of the cellular cleaning systems may be able to stop the progression of Parkinson's disease, the greatest unmet need of patients today.

Anticipated Outcome:
Through these studies we expect to generate one or two drugs capable of enhancing the activity of a specific cleaning mechanism in brain cells. Future studies will be oriented to test the efficacy of these new drugs in reducing neurodegeneration in pre-clinical models of PD. Our ultimate goal would be to generate a drug that could be tested in clinical trials for PD patients.

Final Outcome

During the past year, our laboratories have worked to develop the first prototype drug that will activate a specific cleaning mechanism inside the cells. We have performed chemical optimization on a series of drug candidates to improve their activity, their stability and ability to reach the brain while at the same time avoid any potential toxicity in pre-clinical models.

Our current best drug candidates have improved activity in cell in culture and reach high levels in the brain when administered both through intravenous injection but also orally. They have good metabolic stability that lasts a few hours in blood and longer in the brain. The drug candidates activate the cleaning mechanism in different areas of the brain of pre-clinical models at doses that there is no evidence of potential toxicity. We have found that their effect in CMA activation may be tested directly in the blood as a good read out that will simplify future testing and help with dosage if these compounds or derivatives are eventually used in patients. Having established these milestones, we hope next to use our current best drug candidates or an improved version to evaluate whether they can reduce neurodegeneration in preclinical models of Parkinson's disease.


  • Ana Maria Cuervo, MD, PhD

    Bronx, NY United States

  • Evripidis Gavathiotis, PhD

    Bronx, NY United States

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