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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: 1R41HL160429-01
Agency Tracking Number: R41HL160429
Amount: $361,774.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-01
Award End Date (Contract End Date): 2022-02-28
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: (781) 752-6094
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 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 feasibility 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
indicates a significant reduction in atherosclerotic lesion burden in ApoE-/- mice. 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 I STTR project is to develop the GPR310
pepducin as a collaborative effort between Oasis Pharmaceuticals (Lexington, MA), Tufts Medical Center
(Boston, MA) and Aronora (Portland, OR) that would provide key early milestones to advance the initial
commercial development of the first GPR31 inhibitor as a dual antiplatelet, anti-stroke drug. This feasibility
study would establish the scientific merit of the proposed program by accomplishing the major milestones at
the end of the 6 months of safety and efficacy in a stroke model and PK/PD correlations in two species.The only FDA-approved treatment for thrombotic stroke is tissue plasminogen activator, but it is used in less
than 5% of stroke victims with no noted improvement in survival and with no direct neuroprotective effects.
Here, we provide the blueprint for feasibility studies for the development of the first GPR31 inhibitor as an
effective antiplatelet therapy that provides secondary neuroprotective effects for mitigating against the acute
neurologic sequela of stroke for a potentially more effective and safer alternative option or adjunct to fibrinolytic
therapy in this area of high unmet medical need.

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

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