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Funded Studies

Development of Inhibitors of Alpha-Synuclein Toxicity to Treat Parkinson's Disease

Many of the symptoms of Parkinson’s disease are caused by the death of dopamine (DA) producing neurons that control movement. Alpha-synuclein is a protein which accumulates in the brains of PD patients and is toxic to dopaminergic neurons. Using novel cellular assays, we have discovered lead compounds that prevent the toxicity induced by alpha-synuclein. Our goal is to identify among these lead compounds a new drug candidate that is neuroprotective to halt disease progression in Parkinson patients.
Project Description:
We have implemented cellular assays of alpha-synuclein toxicity and used them to identify lead compounds that prevent cell death. We will extend the testing of these compounds into an animal model of PD in which expression of alpha-synuclein causes progressive neurodegeneration in the substantia nigra, the region of the brain affected in PD patients. To qualify for testing in the PD animal model, lead molecules active in the cellular assays must have several additional characteristics including solubility suitable for administration, good tolerability, and adequate adsorption into brain. To test for efficacy, lead compounds will be administered to rats expressing alpha-synuclein. After six weeks of treatment, the extent of neurodegeneration will be assessed by measuring the concentration of the neurotransmitter DA and the number of surviving dopamine producing neurons. Compounds that mitigate neurodegeneration will be advanced to preclinical optimization, the next step in the drug discovery process.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The current therapies for PD increase the level of the neurotransmitter DA thereby relieving the symptoms but do not address the underlying cause of the disease. By identifying neuroprotective compounds, this project holds the potential to develop a drug that can slow/prevent disease progression.
Anticipated Outcome:
We expect to show that our lead compounds are efficacious as neuroprotective agents in an acute animal model of alpha-synuclein mediated neurodegeneration .Further optimization should lead to the identification of novel neuroprotective drug candidates for the treatment of PD.

Final Outcome

FoldRx identified several leads that reduce alpha-synuclein induced toxicity in a cell culture model and established structure activity relationships for substituent’s at one of the key positions on the scaffold. This information was used to generate more potent and efficacious molecules in vitro. In vivo testing of a subset of compounds generated preliminary data that this chemical series may provide protection in an animal model of alpha-synuclein toxicity.

To facilitate further optimization of the series and to guide compound selection for animal testing, FoldRx has conducted mechanism of action studies during 2009 (supported by a MJFF RIAA) and has identified a biochemical activity that is modulated by compounds in the series. Current efforts are focused on identification and validation of the molecular target.



  • Christine Bulawa, PhD

    Cambridge, MA United States

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