DEVELOPING A TRANSLATABLE PLATFORM FOR REVERSIBLE PLATELET INHIBITION

开发可逆血小板抑制的可翻译平台

• 批准号: 8469091
• 负责人: Richard Clinton Becker
• 金额: $ 92.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469091
• 关键词: Address; Adhesions; Agonist; Antidotes; Antiplatelet Drugs; Arterial Fatty Streak; Biology; Blood Platelets; Blood Vessels; Blood flow; Canis familiaris; Cardiovascular system; Cessation of life; Chemicals; Clinical; Clinical Research; Coagulation Process; Coronary; Cyclic GMP; Data; Defect; Development; Disease; Drug Kinetics; Effectiveness; Engineering; Equipment Malfunction; Genetic; Glycoprotein Ib; Glycoproteins; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Impairment; Ischemic Stroke; Lead; Leucine-Rich Repeat; Ligands; Modification; Mus; Myocardial Infarction; Nucleic Acids; Oligonucleotides; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Platelet aggregation; Procedures; Protein Binding; Protein Family; Proteins; Rattus; Recruitment Activity; Risk; Role; Safety; Shapes; Surface; Thrombosis; Thrombus; Titrations; Toxic effect; Toxicokinetics; United States Food and Drug Administration; adhesion receptor; aptamer; chemical synthesis; healthy volunteer; human study; in vivo; inhibitor/antagonist; knowledge base; novel; phase 1 study; phase 2 study; pre-clinical; prevent; receptor; repaired; shear stress; von Willebrand Factor

Rationale and Overall Objective: Our overall goal is to develop a rapidly reversible antiplatelet agent that inhibits thrombus formation in highly prothrombotic settings such as those encountered during coronary revascularization procedures. Unregulated accumulation of platelets on atheromatous plaques and other thrombogenic surfaces is an absolute prerequisite for thrombus formation, which in turn represents a proximate cause of myocardial infarction, equipment malfunction, ischemic stroke and cardiovascular death(1-3). Antiplatelet drugs represent a direct outgrowth from a rapidly expanding knowledge base of fundamental platelet biology. None of the available antiplatelet therapies prevent the initiating step for thrombus formation- platelet adhesion. Accordingly, developing novel drugs that are engineered specifically to inhibit biologically relevant targets operative in platelet adhesion represents an important step toward addressing an unmet clinical need. Glycoprotein (GP) Ib-IX-V is a platelet adhesion receptor belonging to a leucine-rich repeat family of proteins. Its major function is to initiate platelet aggregation at high-shear stress blood flow, leading to thrombus formation(4). Following GP Ib-lX-V adhesion to von Willebrand Factor (VWF), platelets become activated, undergo cytoskeletal shape change and secrete platelet agonists that recruit additional platelets to the developing thrombus". Along with GP llb/llla, GP Ib-IX-V is the only platelet receptor that has a non-redundant role in hemostasis and thrombosis, with a hemostatic defect less serious than that of GP llb/llla deficiency(4-7). Thus, inhibitors of GP Ib-IX-V - VWF interaction may have the potential to become effective antithrombotic drugs with a more favorable safety proflle than GP llb/llla inhibitors. The overall effectiveness of antithrombotic therapy for managing patients with thrombotic disorders, particularly those requiring either invasive procedures or surgery has been limited in large part by the attendant bleeding risk which accompanies these therapies. While the responsible mechanisms are poorly defined, concomitant impairment of hemostasis and vascular repair have been proposed as likely contributors. We have previously shown that protein-binding oligonucleotides (aptamers), single-stranded nucleic acids that inhibit platelets, their functional ligands and/or coagulation proteins with high speciflcity can be readily reversed with complementary oligonucleotide antidotes(8-10). Of particular relevance to this proposal, we have developed aptamers against VWF that potentiy inhibit thrombosis in mice and antidote oligonucleotides that can rapidly reverse the antiplatelet activity of the aptamers(11) (Sullenger lab unpublished results). This aptamer-antidote strategy potentially offers broad applications, with the development of antithrombotic drugs which could be actively controlled, allowing full pharmacodynamic effects when clinically indicated, followed by rapid titration or complete reversal.

基本原理和总体目标：我们的总体目标是开发一种快速可逆的抗血小板药物，在高度血栓形成的情况下（例如冠状动脉血运重建过程中遇到的情况）抑制血栓形成。血小板在动脉粥样硬化斑块和其他血栓形成表面上不受控制的积聚是血栓形成的绝对先决条件，这反过来又代表了血栓形成的直接原因。 心肌梗塞、设备故障、缺血性中风和心血管死亡的原因(1-3)。 抗血小板药物代表了快速扩展的基础血小板生物学知识库的直接产物。现有的抗血小板疗法都不能阻止血栓形成的起始步骤——血小板粘附。因此，开发专门设计用于抑制血小板粘附中起作用的生物学相关靶标的新药物代表着朝着解决未满足的临床需求迈出的重要一步。糖蛋白 (GP) Ib-IX-V 是一种血小板粘附受体，属于 富含亮氨酸的蛋白质重复家族。其主要功能是在高剪切应力血流下引发血小板聚集，导致血栓形成(4)。 GP Ib-lX-V 粘附到血管性血友病因子 (VWF) 后，血小板被激活，经历细胞骨架形状变化并分泌血小板激动剂，将额外的血小板募集到正在形成的血栓中。”与 GP IIb/IIIa 一样，GP Ib-IX-V 是唯一的血小板受体 在止血和血栓形成中具有非冗余作用，其止血缺陷不如 GP IIb/IIIa 缺陷严重(4-7)。因此，GP Ib-IX-V-VWF相互作用的抑制剂可能有潜力成为有效的抗血栓药物，其安全性比GP IIb/IIIa抑制剂更有利。 抗血栓治疗对于治疗血栓性疾病患者（特别是那些需要侵入性手术或手术的患者）的总体有效性在很大程度上受到伴随这些治疗的出血风险的限制。虽然责任机制定义不明确，但随之而来的 止血和血管修复受损被认为是可能的原因。我们之前已经证明，蛋白质结合寡核苷酸（适体）、抑制血小板的单链核酸、其功能性配体和/或具有高特异性的凝血蛋白可以很容易地用互补的寡核苷酸解毒剂逆转(8-10)。与该提案特别相关的是，我们开发了能够有效抑制小鼠血栓形成的 VWF 适配体，以及能够快速逆转适配体抗血小板活性的解毒寡核苷酸(11)（Sullenger 实验室未发表的结果）。这种适体解毒剂策略 随着可主动控制的抗血栓药物的开发，在临床指征时实现充分的药效作用，然后快速滴定或完全逆转，潜在地提供了广泛的应用。