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

脂质受体 GPR31 作为抗血栓和中风治疗的靶点

基本信息

批准号：
10603440
负责人：
Athan Kuliopulos
金额：
$ 99.98万
依托单位：
OASIS PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603440
关键词：
Acceleration Acute Adult Adverse effects Alteplase Arachidonate 12-Lipoxygenase Area Biological Assay Blood Platelets Boston Brain Edema Canis familiaris Cardiovascular system Cause of Death Cell Death Cells Central Nervous System Cerebrovascular Disorders Chemistry Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Coagulation Process Coupled Cytochrome P450 Data Development Disabled Persons Dose Enzyme Induction Enzyme Inhibition Enzymes FDA approved Fatty Acids Formulation G-Protein-Coupled Receptors GPR31 receptor GTP-Binding Proteins Genetic Glucose Glutamates Goals Grant Hemorrhage Hemostatic function Hepatic Hydroxyeicosatetraenoic Acids Hypertension Implant Individual Infarction Inflammation Inflammatory Infusion procedures Intracranial Hemorrhages Intravenous Ischemic Stroke Knockout Mice Lipids Mediating Medical Medical center Membrane Metabolism Modeling Molecular Target Mus Mutation Neurologic Neurology Neurons Orphan Oxidative Stress Oxygen Papio Pathologic Penetration Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Phase Phase I Clinical Trials Phenocopy Physiological Primary Prevention Production Program Development Prostate Rattus Recovery Reporting Risk Factors Role Safety Series Signal Transduction Signaling Molecule Small Business Technology Transfer Research Specificity Stroke Symptoms Technology Telemetry Therapeutic Thrombolytic Therapy Thrombosis Thrombotic Stroke Time Tissue Model Tissues Toxic effect Toxicology Validation Water acute stroke antagonist clinical effect commercialization cost estimate design disability drug development efficacy evaluation experimental study first-in-human improved inhibitor manufacture meetings method development mouse model neuron loss neuroprotection oxidation phase 1 study post stroke pre-clinical protective effect receptor respiratory safety assessment side effect stroke model stroke patient stroke therapy stroke victims thrombotic

项目摘要

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.

尽管普遍使用抗血小板和抗脂质治疗，中风仍然是第三大死亡原因