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Lipid Receptor GPR31 as a Target for Anti-Thrombotic and Stroke Therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42HL160429-02
Agency Tracking Number: R42HL160429
Amount: $999,799.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA21-262
Solicitation Year: 2021
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-02-01
Award End Date (Contract End Date): 2025-01-31
Small Business Information
Lexington, MA 02420-1226
United States
DUNS: 968691712
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (617) 636-8482
Business Contact
Phone: (617) 636-8482
Research Institution
BOSTON, MA 02111-1552
United States

 Domestic Nonprofit Research Organization

Despite prevalent use of anti-platelet and anti-lipid therapies, stroke remains the third major cause of death
and is the leading cause of adult disability in the US with an estimated cost in the range of $34 billion
annually. Approximately 20% of the annual 795,000 stroke patients die within one year and 15-30% are
permanently disabled. Antiplatelet therapy is mainly used for primary prevention of acute ischemic stroke in
cerebrovascular disease. Bioactive fatty acids are a new class of molecular targets that hold great
therapeutic potential because of their diverse role as signaling molecules that regulate metabolism and
inflammation. The oxidation of arachidonic acid by 12-LOX results in the production of a number of bioactive
lipids including the metabolite 12(S)-HETE. The lipid receptor GPR31, an orphan class A GPCR, is a 12(S)-
HETE receptor recently shown to be involved in inflammatory signaling. We recently discovered that GPR31
mediates 12(S)-HETE prothrombotic signaling in platelets and promotes glutamate-induced oxidative
toxicity in neuronal cells. Therefore, we propose that targeting GPR31 may provide a therapeutic path
towards development of a safe and effective antiplatelet therapy that is coupled with secondary
neuroprotective effects for mitigating against the acute neurologic sequela of stroke to provide a more
effective and safer alternative option or adjunct to fibrinolytic therapy. We have recently succeeded in
identifying the first effective GPR31 antagonist using our cell-penetrating, membrane-tethered, Pepducin
technology to be validated in these preclinical IND-enabling studies as an anti-platelet and anti-stroke
agent. We show here that this i3-loop derived GPR31 lipopeptide has potent antiplatelet activity and nearly
completely suppresses arterial thrombosis without an effect on hemostasis in mice. Preliminary data with
the GPR310 pepducin shows a highly significant reduction in stroke infarct area in mice similar to the
protective effect of Gpr31-deficiency. Furthermore, we provide evidence for a direct neuroprotective effect of
the GPR310 pepducin on HT22 neuronal cells subjected to glutamate mediated oxidative stress. The goal
of this Phase 2 STTR project is to develop the GPR310 pepducin as a collaborative effort between Oasis
Pharmaceuticals (Lexington, MA), Tufts Medical Center (Boston, MA) that would provide a robust IND data
package required to advance the initial commercial development of the first GPR31 inhibitor as a dual
antiplatelet, anti-stroke drug. This drug development program would establish the scientific merit of the
GPR31 target by accomplishing the major milestones at the end of 2 years of GLP safety/pharmacology
and efficacy in stroke models ± thrombolytic therapy to support a Phase I first-in-human clinical trial.

* Information listed above is at the time of submission. *

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