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，但中风仍然是第三个主要死亡原因这是美国成人残疾的主要原因，估计成本在340亿美元之间在一年内，每年795,000名中风患者死亡，大约有20％，而15-30％永久残疾。抗血小板疗法主要用于主要预防急性缺血性中风脑血管疾病。生物活性脂肪酸是一类新的分子靶标，可保持良好治疗潜力是因为它们作为调节代谢和调节代谢的信号分子的作用分歧炎。 12-lox将花生四烯酸氧化导致许多生物活性的产生脂质在内，包括代谢物12（s） - hete。脂质受体GPR31是A级A类GPCR，是12（s） - Hete受体最近证明与炎症信号传导有关。我们最近发现GPR31 介导血小板中的12（s） - hete促血栓形成信号传导，并促进谷氨酸诱导的氧化作用神经元细胞的毒性。因此，我们建议靶向GPR31可能提供治疗路径旨在开发安全有效的抗血小板疗法，该疗法与次级结合神经保护作用可缓解急性中风的急性神经系统续集，以提供更多有效，更安全的替代选择或纤维蛋白水解疗法的辅助手段。我们最近成功了使用我们的细胞渗透，膜系，腹膜蛋白识别第一个有效的GPR31拮抗剂在这些临床前的核对研究中，要验证的技术是抗血域和抗震动的技术代理人。我们在这里表明，这种I3环衍生的GPR31脂蛋白肽具有潜在的抗血小板活性，几乎完全抑制了伪像，对小鼠的止血没有影响。初步数据 GPR310浮力素显示出类似于小鼠的小鼠中风梗塞区域的显着降低 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遍布蛋白蛋白蛋白受到谷氨酸介导的氧化应激。目标该阶段2的STTR项目是开发GPR310遍布pepducin作为绿洲之间的协作努力 Pharmaceuticals（马萨诸塞州列克星敦），塔夫茨医疗中心（马萨诸塞州波士顿），将提供强大的IND数据推进第一个GPR31抑制剂的初步商业开发所需的包装抗血小板，抗中风药物。该药物开发计划将确立 GPR31目标是在GLP安全/药理学2年结束时完成主要里程碑在中风模型±溶栓疗法中有效，以支持I期第一阶段的人类临床试验。