Inhibition of Striatal-enriched Phosphate (STEP) to Improve Parkinson-related Cognitive Dysfunction

Promising Outcomes of Original Grant:
Our original funded project was designed to examine absorption and distribution of the STEP (Striatal-Enriched Phosphatase), a protein associated with several neurological disorders, inhibitor TC-2153 and demonstrate activity of this drug following oral administration to pre-clinical models of Parkinson's disease (PD). The study found that, following oral administration of the drug, a time-dependent increase in STEP inhibition was observed, demonstrating that TC-2153 is present in blood and is biologically active.

Objectives for Supplemental Investigation:
Previous data have demonstrated the ability of the STEP inhibitor TC-2153 to improve cognitive deficits in pre-clinical models of aging and Alzheimer's disease. There are also preliminary data that show an increase in STEP in a Parkinson's pre-clinical model, in which there are cognitive deficits, and in tissue from those with PD. Our hypothesis is that STEP is abnormally elevated in parkinsonian models with cognitive deficits and that STEP inhibition will improve cognitive function in these models.

Importance of This Research for the Development of a New PD Therapy:
This is the first time that increased expression of STEP has been associated with cognitive dysfunction in PD. The objective of this study is to provide preliminary proof-of-concept data to support future studies of a potential new treatment approach to PD that might combine therapies aimed at the dopamine system to maximize motor symptom relief with a STEP inhibitor to potentially improve cognition. This approach could have significant drug development and clinical impact.