Histone deacetylases (HDACs) are a family of enzymes that reduce gene expression and can regulate protein clearance. Inhibitors of HDACs have been reported to be efficacious in cellular and pre-clinical models of Parkinson’s disease. The goal of our project is to test a novel HDAC inhibitor in two different models of Parkinson’s disease. The inhibitor, EVP-0334, is active orally, enters the brain and is in clinical development.
This proposal will test EVP-0334 in the MPTP pre-clinical model and in an alpha-synuclein transgenic pre-clinical model of Parkinson’s disease. The studies with MPTP will assess the efficacy of EVP-0334: 1) to protect dopaminergic neurons when EVP-0334 is given prior to the neurotoxin; 2) to restore neuronal function when it is administered after exposure to MPTP has started; and 3) to prevent neuronal loss and restore function that is impaired by chronic, as well as acute exposure to MPTP.
In the alpha-synuclein transgenic model experiments, EVP-0334 will be administered to transgenic models for six months, between the ages of 6 and 12 months, and the activity of the compound in several parameters including neuronal death and neuroinflammation will be determined.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Demonstration of neuroprotective or neurorestorative activity by EVP-0334 in these models would suggest that HDAC inhibition in general, and EVP-0334 in particular, holds promise as a treatment that could slow the progression of Parkinson’s disease. Since EVP-0334 is in early clinical development, a clinical trial testing the efficacy of EVP-0334 in Parkinson’s disease patients could be initiated relatively quickly should these pre-clinical experiments prove positive.
These experiments will help assess the potential for HDAC inhibition in the treatment of Parkinson’s disease. In addition, they will provide insight into when during the course of the disease HDAC inhibition may be most effective. If these studies are positive, a clinical trial in Parkinson’s disease patients with EVP-0334 may be initiated. Finally, the studies will increase the interest of academic scientists and pharmaceutical companies to further explore the role of HDACs in the pathophysiology of Parkinson’s disease.
The HDAC inhibitor FRM-0334 and sodium phenylbutyrate, a reference HDAC inhibitor, given up to seven days before MPTP treatment and daily thereafter for seven days, had no effect on outcome measures in the MPTP-model of Parkinson’s disease. The lack of efficacy of the reference compound in our study highlights the importance of the dosing schedule relative to toxin application. A more recent publication showed that dosing of sodium phenylbutyrate more than three hours after the last MPTP dose (rather than 1.5 hours before MPTP as in our study) improved delayed functional outcomes (Roy et al., 2012).
We evaluated 8-month-old pre-clinical models expressing normal human alpha-synuclein under the PDGF promoter (Masliah et al., 2000) in a large battery of behavioral and immune-histochemical assays. FRM-0334 displayed positive effects on the two principal clinical types we observed, decreasing significantly synucleinopathy in the hippocampus and cortex and tending to improve deficits in the Challenging Beam Walk motor test. The effects on alpha-synuclein were not due to reduced expression of alpha-synuclein mRNA. Overall, our data indicate that the models that have mild disease traits could potentially be treated by FRM-0334. Our results warrant further investigation of the mechanism by which HDAC inhibition is affecting alpha-synuclein accumulation.