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

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).

Grant Number: 1RF1AG079890-01A1
NIH Institute/Center: NIH
Principal Investigator: Nabil Alkayed