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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疗法，中风仍然是第三大死亡原因是美国成人残疾的主要原因，估计造成的损失达 340 亿美元每年。每年 795,000 名中风患者中，约有 20% 在一年内死亡，其中 15-30% 死于中风。永久禁用。抗血小板治疗主要用于急性缺血性脑卒中的一级预防脑血管疾病。生物活性脂肪酸是一类新的分子靶标，具有很大的用途由于它们作为调节代谢和代谢的信号分子的多种作用，具有治疗潜力炎。 12-LOX 氧化花生四烯酸会产生许多生物活性物质脂质，包括代谢物 12(S)-HETE。脂质受体 GPR31 是一种孤儿 A 类 GPCR，是一种 12(S)- HETE 受体最近被证明参与炎症信号传导。我们最近发现 GPR31 介导血小板中的 12(S)-HETE 血栓前信号传导并促进谷氨酸诱导的氧化对神经细胞的毒性。因此，我们提出靶向GPR31可能提供一条治疗途径致力于开发一种安全有效的抗血小板治疗，并与二次治疗相结合减轻中风急性神经系统后遗症的神经保护作用，提供更多有效且更安全的替代选择或纤溶治疗的辅助疗法。我们最近成功地使用我们的细胞穿透性膜束缚 Pepducin 鉴定第一个有效的 GPR31 拮抗剂该技术将在这些临床前 IND 研究中作为抗血小板和抗中风药物进行验证代理人。我们在此表明，这种 i3 环衍生的 GPR31 脂肽具有有效的抗血小板活性，并且几乎完全抑制动脉血栓形成，且不影响小鼠的止血效果。初步数据与 GPR310 pepducin 显示小鼠中风梗塞面积的显着减少，与 Gpr31 缺陷的保护作用。此外，我们提供了直接神经保护作用的证据 HT22 神经元细胞上的 GPR310 pepducin 受到谷氨酸介导的氧化应激。目标该 STTR 项目第 2 阶段的目标是开发 GPR310 pepducin，作为 Oasis 和 Oasis 之间的合作制药公司（马萨诸塞州列克星敦）、塔夫茨医疗中心（马萨诸塞州波士顿）将提供可靠的 IND 数据推进第一个 GPR31 抑制剂作为双药的初步商业开发所需的软件包抗血小板、抗中风药物。该药物开发计划将确立该药物的科学价值 GPR31 目标是在 GLP 安全性/药理学 2 年后完成主要里程碑和中风模型的疗效±溶栓治疗，以支持 I 期首次人体临床试验。