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，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毒性神经元细胞。因此，我们建议靶向 GPR31 可能提供一条治疗途径开发安全有效的抗血小板疗法并结合二级神经保护减轻中风急性神经系统后遗症的效果，提供更有效、更安全的治疗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、膜束缚、Pepducin 技术的有效 GPR31 拮抗剂在这些临床前可行性研究中作为抗血小板和抗中风药物得到了验证。我们在这里表明这种 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，但对小鼠止血没有影响。 GPR310 pepducin 的初步数据表明 ApoE-/- 小鼠的动脉粥样硬化病变负担显着减少。此外，我们还提供 GPR310 pepducin 对 HT22 神经元细胞具有直接神经保护作用的证据谷氨酸介导的氧化应激。 STTR第一期项目的目标是开发GPR310 pepducin 是 Oasis Pharmaceuticals（马萨诸塞州列克星敦）和塔夫茨医疗中心之间的合作成果（马萨诸塞州波士顿）和阿罗诺拉（俄勒冈州波特兰）将提供关键的早期里程碑，以推进最初的第一个 GPR31 抑制剂作为双重抗血小板、抗中风药物的商业开发。这个可行性研究将通过实现主要里程碑来确定拟议计划的科学价值中风模型的安全性和有效性以及两个物种的 PK/PD 相关性的 6 个月结束。