Several lines of evidence point to the therapeutic potential of Retinoic acid (RA), a metabolite of vitamin A, in the treatment of Parkinson’s disease. For example, RA treatment conferred higher tolerance to neurotoxicity and oxidative stress in a model of PD. RA synthesis deficiency has also been associated with nonhereditary and hereditary forms of PD. Because RA induces its own breakdown, a loss of activity is expected during long-term treatment. The proteins mediating retinoic acid breakdown are named CYP26. Of the three CYP26 identified clearing RA, CYP26B1 appears to be the predominant brain type.
We hypothesize that selective inhibition of CYP26B1 in the brain will increase neuronal RA concentrations and will reduce loss of dopaminergic function associated with PD, providing a therapeutic advantage for PD patients.
We will optimize activity and selectivity of our previously identified CYP26B1 inhibitors. Then we will demonstrate their neuroprotective effects in dopaminergic neuron cultures and show their ability to increase retinoic acid brain concentration. By the end of this project, we will have identified a safe, first-in-class lead compound that selectively inhibits CYP26B1, decreasing RA breakdown in brain.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This study will generate the data necessary to further refine this new and unique therapeutic approach for the management and treatment of Parkinson’s disease.
Next Steps for Development:
Using the combined data generated in this project, we will complete safety studies for the selected CYP26B1 inhibitor and study efficacy of this new therapeutic strategy.
In this study we have optimized the activity and selectivity of our previously identified CYP26B1 inhibitors.
We demonstrated that our compounds have the ability to increase retinoic acid concentration in cells. We
have designed a drug delivery system to administer our compounds in vivo in order to complete safety and
efficacy studies. The preliminary in vivo toxicological studies have demonstrated that our series of
compound is safe. Hence, we have identified safe, first-in-class lead compounds that selectively inhibits
CYP26A1 or CYP26B1 or both CYP26A1 and B1 ready for efficacy studies.