Objective/Rationale:
The Glucagon-Like-Peptide-1 (GLP-1) receptor agonist, exendin-4 (exenatide injection; brand name Byetta) is an FDA-approved, first-in-class treatment for patients with Type 2 Diabetes Mellitus. Recent studies have demonstrated the neuroprotective and pro-neurogenic activities of exendin-4 as well as the ability of exendin-4 to markedly attenuate the neurobehavioral, neurochemical, and histopathological deficits in multiple rodent models of PD. Exendin-4 has the potential to modify disease progression in PD patients.
Project Description:
The efficacy of exendin-4 in a pre-clinical model of PD will be determined, and an optimal dose regimen that is safe and effective will be identified. A manuscript describing the effects of exendin-4 on multiple therapeutic endpoints, including neurobehavioral recovery, restoration of dopamine imbalance in the striatum, and the histopathological improvement of nigrostriatal dopamine neurons, will be prepared and submitted to a peer-reviewed journal. In addition, the efficacy of exendin-4 in a pre-clinical model of PD will be determined, and the mechanism of exendin-4’s effects will be tested. Positive data will support a decision to test the efficacy of exendin-4 in a non-human primate model of PD to further justify clinical testing of exendin-4 in PD patients.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently there is no proven therapy to reduce the rate of progression of PD. Exendin-4 is potentially unique because it has both neuroprotective and neurogenic activities in vivo, it has been shown to have robust efficacy in multiple rodent models of PD, and it is already an FDA-approved diabetes drug, substantially shortening the time to NDA approval for treatment of PD.
Anticipated Outcome:
This grant will support the execution and peer-reviewed publication of a set of non-clinical studies of the efficacy and mechanism of action of exendin-4 in rodent models of PD. Positive data may support an IND application to the FDA to initiate Phase 2a clinical studies of exendin-4 in PD patients.
Progress Report
The goal of this project was to replicate the published findings on exendin-4 in two pre-clinical models using Amylin-manufactured exenatide (exendin-4) and to compare the efficacy of intermittent vs. continuous administration of exendin-4. Exendin-4 at multiple doses, both intermittent and continuous, failed to significantly improve neurobehavioral or neurochemical endpoints in the two PD models. Experiments aimed at understanding the discrepancies between the present findings and those previously published are ongoing.