Objective/Rationale:
This is a collaborative research project between three organizations, NIDA, NIA and Pfizer, focused towards characterizing whether gliptins, a well-tolerated drug class effective in the clinical treatment of type 2 diabetes, would be useful in Parkinson’s disease (PD). The focus is to quantify the neurotrophic and neuroprotective actions of three clinically approved gliptins and the Pfizer experimental drug, PF-00734,200, in well-characterized cellular and pre-clinical models of PD to define potential for the clinical repositioning of this treatment strategy for PD.
Project Description:
The Pfizer experimental drug PF-00734,200, similar to other gliptin drugs, is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), the primary enzyme catalyzing the metabolism of the endogenous incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). PF-00734,200 was developed by Pfizer for the treatment of type 2 diabetes mellitus (T2DM) and showed efficacy and tolerability in phase 2 clinical trials. Inhibition of DPP-4 elevates circulating levels of GLP-1 and GIP, particularly after food ingestion when their levels peak. GLP-1 and GIP interact with their receptors on pancreatic cells to lower blood glucose levels. Receptors for these incretins are also present on neurons in brain, and their activation has been associated with potent neuroprotective and neurotrophic actions. Our research will define whether well-tolerated gliptin-induced DPP-4 inhibition provides, (i) neuroprotective benefit in cellular and pre-clinical models of PD and, (ii) neuroregenerative benefit when administered after the establishment of PD. The focus of our research is to test the hypothesis that gliptin-induced DPP-4 inhibition is a useful treatment strategy for PD and to assess whether it is sufficiently efficacious to warrant the repositioning of PF-00734,200 toward the treatment of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Currently, therapeutic strategies to treat and alter the progression of PD are in great need. We hypothesize that gliptin-induced DPP-4 inhibition may, either by elevating endogenous levels of GLP-1 and GIP systemically and in brain or via a direct action, promote synaptic function, ameliorate dopaminergic cell loss and/or aid regenerative process occurring in PD, each of which – individually or combined – may be of clinical value in PD. Furthermore, as 50-80% of PD patients have abnormal glucose tolerance, DPP-4 inhibition may concurrently ameliorate metabolic and neuronal dysfunction.
Anticipated Outcome:
The proposed studies are aimed to critically assess in well-characterized pre-clinical models whether DPP-4 inhibition will provide a new PD treatment strategy. A well-tolerated drug class, gliptins, which has shown efficacy in the treatment of T2DM is the focus of research, to support rapid repositioning and translation to PD patients.
Progress Report
Collaborative NIDA, NIA and Pfizer studies are evaluating the potential of gliptins, a well-tolerated drug class effective in the medication of type 2 diabetes, as a new treatment strategy for Parkinson’s disease (PD). These drugs inhibit the enzyme dipeptidyl peptidase-4, responsible for metabolizing the endogenous incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Our cellular studies have demonstrated that GLP-1 and GIP separately and, especially, together protect neurons from toxic insults pertinent to PD, particularly when combined with the Pfizer gliptin, PF-00734,200. Our studies in pre-clinical models administered PF-00734,200 or one of three available clinically approved gliptins are defining elevations in blood and brain GLP-1 and GIP levels, and are relating these to measured drug levels. These studies highlighted PF-00734,200 as an agent worthy of assessing in parkinsonism models, and are guiding our selection of the best available clinically approved gliptin to move forward as a comparator. Studies to define whether PF-00734,200 acts as a neuroprotective agent in mdoels with chemically induced parkinsonism are ongoing and preliminary data appears promising. Planned research will extend these studies with PF-00734,200 and the comparator gliptin, and will assess for neuroregenerative actions in well-characterized pre-clinical PD models. Our focus is to critically evaluate whether gliptins hold promise for PD and, if so, to select the best available agent for clinical translation.
July 2012
Final Outcome
Neuronal cell culture studies have demonstrated that GLP-1 and GIP separately and together protect neurons from toxic insults pertinent to PD, especially when combined with a gliptin. Studies in pre-clinical models administered a Pfizer experimental gliptin or one of several available clinically approved gliptins evaluated brain drug entry, and elevations in blood and brain GLP-1 and GIP levels. From these studies, two gliptins were evaluated in parkinsonism models to define whether they afford neuroprotective and neuroregenerative actions across a wide number of quantitative measures. The research focus has been to critically evaluate whether gliptins hold promise for PD and select a candidate agent for potential clinical translation.
December 2013