GPR39 as a Therapeutic Target in Aging-Related Vascular Cognitive Impairment and Dementia

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PROJECT SUMMARY The number of individuals with dementia, estimated at 57.4 million cases worldwide, is expected to triple by 2050 at a cost approaching $4 trillion due to aging of the world population. Aging-related vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer's disease (AD). The mechanisms underlying VCID are not well understood, with no specific therapies currently available to prevent or treat VCID. We have previously found increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem dementia and postmortem histopathological evidence of cerebral small vessel disease. Transgenic mice expressing the human sEH gene under the endothelial Tie2 promoter (Tie2-hsEH) exhibit age-dependent cognitive deficit, supporting a causal link between endothelial sEH upregulation and cognitive impairment. sEH is responsible for the breakdown of 14,15-epoxyeicosatrienoate (14,15-EET), an endogenous lipid signaling molecule with vasodilator properties that preferentially acts on small blood vessels. We recently identified G protein-coupled receptor 39 (GPR39) as a molecular target for 14,15-EET localized in human and mouse brains in peri-capillary pericytes. The goal of this application is to develop a first-in-class, CNS-penetrant small molecule GPR39 agonist as a treatment for VCID. We have completed high-throughput screening (HTS) of a small- molecule library containing more than 250,000 compounds that identified several promising compounds with high selectivity, potency and drug-like properties. The proposed studies will use multiple in-vitro and in-vivo assays to identify lead compounds (Hit-to-Lead; Aim 1), determine their safety and efficacy in mouse models of VCID induced by aging and chronic cerebral hypoperfusion (CCH; Preclinical Testing; Aim 2), and optimize them for oral bioavailability (Lead Optimization; Aim 3). The proposed studies are highly significant, translational and innovative. There is currently an unmet medical need for a safe and effective therapy for VCID, based on the growing number of patients with VCID due to population aging, lack of disease-modifying therapy, and the psychological, social and economic burden of VCID. We propose to develop a small molecule therapeutic that targets a novel mechanism for VCID involving a novel receptor (GPR39) and cell type (peri-capillary pericytes).