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：
10325956
负责人：
Athan Kuliopulos
金额：
$ 36.18万
依托单位：
OASIS PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325956
关键词：
Acute Adult Adverse effects Alteplase Animal Model Apolipoprotein E Apoptosis Arachidonate 12-Lipoxygenase Arachidonic Acids Area Arterial Fatty Streak Atherosclerosis Biological Availability Blood Platelets Boston Brain Edema Calcium Cause of Death Cell Death Cells Cerebrovascular Disorders Coronary Coupled Data Development Diet Disabled Persons Dose Enzymes F2R gene FDA approved Fatty Acids Feasibility Studies Formulation Free Radicals G-Protein-Coupled Receptors GPR31 receptor GTP-Binding Proteins Glucose Glutamate Receptor Glutamates Goals Hemorrhage Hemostatic function Human Hydroxyeicosatetraenoic Acids Hypertension Infarction Inflammation Inflammatory Intervention Intracranial Hemorrhages Ischemic Stroke LOX gene Lesion Lipids Mediating Medical Medical center Membrane Metabolism Modeling Molecular Target Mus Neurologic Neurons Oregon Orphan Oxidative Stress Oxygen Papio Pathologic Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase II Clinical Trials Physiological Platelet Activation Primary Prevention Production Prostate Reporting Risk Factors Rodent Role Safety Series Signal Transduction Signaling Molecule Small Business Technology Transfer Research Stroke Symptoms Technology Testing Therapeutic Thrombolytic Therapy Thrombosis Thrombotic Stroke Time Tissues Toxic effect Toxicology acute stroke cost estimate disability in vivo inhibitor/antagonist ischemic injury mouse model neuron loss neurotoxicity nonhuman primate oxidation pharmacokinetics and pharmacodynamics post stroke pre-clinical programs protective effect receptor recruit stroke model stroke patient stroke therapy stroke victims subcutaneous

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 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.

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340亿美元之间每年。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新陈代谢和的信号分子的作用多样炎。 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毒性神经元细胞。因此，我们建议针对GPR31的靶向可能为通往开发安全有效的抗血小板疗法，该治疗与继发性神经保护作用缓解急性卒中急性神经系统后遗症的影响，以提供更有效，更安全的纤溶治疗的替代选择或辅助疗法。我们最近成功地确定了第一个使用我们的细胞穿透，膜系，腹膜蛋白技术的有效GPR31拮抗剂是在这些临床前可行性研究中被验证为抗血域和抗震动剂。我们在这里表明这种I3环衍生的GPR31脂蛋白肽具有有效的抗血小板活性，几乎完全抑制动脉血栓形成对小鼠止血没有影响。 GPR310浮力素的初步数据表明APOE - / - 小鼠的动脉粥样硬化病变负担显着减轻。此外，我们提供 GPR310遍布pepducin对遭受HT22神经元细胞的直接神经保护作用的证据谷氨酸介导的氧化应激。该阶段I STTR项目的目标是开发GPR310 浮游生物作为Oasis Pharmaceuticals（马萨诸塞州列克星敦），塔夫茨医疗中心之间的合作努力（马萨诸塞州波士顿）和阿罗诺拉（波特兰，俄勒冈州），将提供关键的早期里程碑来推进初始第一个GPR31抑制剂的商业开发是双重抗血小板，抗中风药物。这种可行性研究将通过在在两个物种中，中风模型和PK/PD相关性的6个月的安全性和功效的结束。