Novel Fumarate Esters as Neuroprotective Agents in Parkinson’s Disease

Objective/Rationale:
Fumaric acid esters have shown immuno-modulatory and neuroprotective effects in cell-based systems,  pre-clinical models of disease and clinical trials in multiple sclerosis and psoriasis patients.  The biological mechanisms underlying these beneficial effects may also be relevant for slowing or stopping neurodegneration caused by Parkinson’s disease.  A shortcoming of existing fumaric acid ester therapies is that patients can suffer from gastrointestinal (GI) adverse events.  XenoPort is developing a novel fumaric acid ester, which has shown reduced gastric irritation in pre-clinical models.  We would like to test this novel compound in a model of neurodegeneration in Parkinson’s disease.

Project Description:
We will examine this compound for its ability to prevent or decrease neurodegeneration in a pre-clinical model in which the neurotoxin MPTP selectively attacks dopamine neurons like those affected by Parkinson’s disease.  One of the important questions we will probe in this study is how the timing of the treatment can effect the progression of neurodegeneration in this model.  Various treatment regimens will be examined to determine if this kind of treatment can prevent damage once neurodegenerative processes have occurred.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current treatments for Parkinson’s disease are able to reduce the symptoms of the disease but are not able to treat the underlying neurodegenerative processes that lead to a decline in physical and cognitive functions that affect some patients with Parkinson’s disease.  An oral drug that could slow or prevent neurodegeneration might be able to decrease the disability progression that some patients experience in the disease.  By identifying markers of neuroinflammation that are affected by XenoPort’s novel fumaric acid ester in this study, we may be able to identify which patients would most likely benefit from such a treatment.

Anticipated Outcome:
If this project is successful, it would provide the first evidence that fumaric acid esters have the potential to slow or prevent the neurodegeneration that occurs in Parkinson’s disease.  The investigation of  the timing required for beginning treatment during the course of the neurodegeneration model could give us information as to when in the progression of Parkinson’s disease it would make sense to begin such a treatment.  This could aid the design of trials that could test fumaric acid esters clinically in Parkinson’s disease patients for their ability to prevent disease progression.