Objective/Rationale:
Parkinson’s dsease is caused by the death of brain dopaminergic neurons that are essential for controlling movement. While the exact cause of PD is not known, there is evidence that mitochondria may be particularly stressed in dopaminergic cells. A number of environmental toxins that produce symptoms remarkably like PD and several genes associated with familial PD lead to mitochondrial malfunction. Therefore, drugs that protect mitochondria could be useful in treating PD.
Project Description:
Trophos has identified and developed a family of compounds based on their ability to rescue motor neurons in both cell and animal models of motor neuron degeneration. After extensive investigation into their mechanism of action, Trophos found that compounds in this family bind to mitochondrial proteins and maintain mitochondrial functions in cells subjected to various types of stress. Since mitochondrial stress and malfunction are underlying conditions in PD, it is of interest to test these compounds in an animal model of PD. Dr. Marie-Francoise Chesselet’s team at UCLA has documented early PD-like behavioral changes in mice carrying the mutated human a-synuclein gene, one of the genes associated with familial PD. These mice may provide an accurate model of neuronal malfunction that precedes cell death where a neuroprotective compound may show activity. Trophos and Dr. Chesselet’s team will collaborate to test two compounds in this pre-clinical model of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The two Trophos compounds to be studied have been extensively characterized and one of them has already demonstrated a very good safety profile in human clinical trials. Should either compound show potential therapeutic benefit in the PD animal model they could rapidly progress to clinical testing in PD patients.
Anticipated Outcome:
Providing evidence that one of Trophos’ compounds that maintain mitochondrial function has a beneficial effect in a clinically relevant PD animal model may identify a new therapeutic strategy for PD and perhaps neurodegeneration in general.
Final Outcome
Mitochondrial dysfunction triggered by alpha synuclein overexpression, possibly combined with oxidative stress or calcium-overload, may be involved in both sporadic and inherited forms of Parkinson’s disease (PD). Trophos has discovered a novel family of compounds that exhibit cytoprotective activity in diverse preclinical models of cell-stress in which mitochondrial dysfunction increases the probability of cell death. Two different members of this chemical family were tested in a pre-clinical model that over-expresses the human alpha-synuclein gene, with behavioral, histological and gene expression profiling performed after 1-3 months of treatment beginning when mice were 1 month old.