Development of the Plasmin-independent Thrombolytic Agent for the Treatment of Acute Ischemic Stroke

开发用于治疗急性缺血性中风的非纤溶酶依赖性溶栓剂

• 批准号: 10384173
• 负责人: Hyeon Jin Kim
• 金额: $ 44.96万
• 依托单位: SNJ PHARMA INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-03 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384173
• 关键词: Acute; Advanced Development; Animal Model; Animals; Biological Assay; Blood; Blood Circulation; Blood coagulation; Brain; Cardiovascular Diseases; Cerebrum; Cessation of life; Clinical; Coagulation Process; Contracts; DegP protease; Development; Doctor of Philosophy; Effectiveness; Enzymes; Evaluation; Evaluation Studies; Excision; Exhibits; Fibrinolytic Agents; Generations; Goals; Guidelines; Hemorrhage; Hemostatic Agents; Hemostatic function; High temperature of physical object; Hour; In Vitro; Incidence; Injections; Intravenous; Investigational New Drug Application; Ischemic Stroke; Laboratories; Lead; Lesion; Manufacturer Name; Mediator of activation protein; Methods; Modeling; Mus; Myocardial Ischemia; Names; Outcome; Pathologic; Pathology; Peptide Hydrolases; Phase; Physiological; Plasmin; Plasminogen; Process; Proteins; Publications; Pulmonary Embolism; Recombinant Proteins; Recombinants; Reperfusion Therapy; Reproducibility; Research; Risk; Specificity; Stroke; Study models; Tail; Technology Transfer; Testing; Therapeutic; Thrombectomy; Thrombin; Thromboembolism; Thrombolytic Therapy; Thrombosis; Thrombus; Toxic effect; Treatment Efficacy; Work; analog; effectiveness evaluation; efficacy testing; endovascular thrombectomy; enzyme activity; improved; improved outcome; in vivo; mortality; mouse model; novel; preclinical efficacy; preservation; process optimization; product development; programs; research clinical testing; scale up; side effect; stroke model; stroke patient; success; therapeutic candidate; thrombolysis; tissue injury; venous thromboembolism; wound; wound healing

Project Summary Thrombosis caused by intravascular blood clots is the most common underlying pathology of the three major cardiovascular disorders: ischemic heart disease, stroke, and venous thromboembolism. The significantly high incidence rate, as well as its fatal consequences, has called the search for safe and effective thrombolytic enzymes, which remained extensive throughout the past several decades. Despite the effort, current thrombolytics have significant drawbacks, including bleeding complications. All the current thrombolytic agents are involved in the activation of plasminogen to plasmin. Unfortunately, the non-specific proteolytic activity of plasmin degrades essential proteins involved in hemostasis and wound healing. Thus, the clinical use of plasmin- dependent thrombolytic therapy has been limited, requiring the initiation of treatment within 3 hours from stroke onset to avoid fatal hemorrhagic complications. A need for new thrombolytics remains urgent for improved treatment without concerns of hemorrhage and tissue injury complications. SNJ Pharma, Inc. identified HtrA1 (high-temperature requirement A1, named as thrombase) that appears to exert strong thrombolytic activity on intravascular clots while permitting normal wound healing. Unlike all currently available thrombolytics, HtrA1 protease does not activate plasminogen to plasmin, a non-specific protease responsible for fatal hemorrhagic complications from thrombolytic therapy. The high specificity of HtrA1 enzyme activity enables selective degradation of pathological thrombi while preserving hemostatic clots, removing the risk of massive bleeding. In vivo murine models, including wound excision and tail bleeding assays, demonstrated that animals treated with HtrA1 exhibited no damage in wound healing in contrast to current thrombolytics. In addition, HtrA1 administration completely dissolved blood thrombi in mice with tail thrombosis and intravascular thrombi in mice with pulmonary embolism when administrated intravenously, resulting in rescued thromboembolism. Here, upon confirming the specificity of HtrA1 activity and preservation of beneficial hemostatic clots, we aim to evaluate the therapeutic efficacies of HtrA1 protease and its potential for the treatment of acute ischemic stroke (AIS) using in vitro thrombectomy model and in vivo photothrombotic AIS model. Our successful completion of this proposal with the first plasmin-independent thrombolytic enzyme will present HtrA1 protease as a revolutionary therapeutic candidate for AIS without the drawback of a limited treatment window in the absence of hemorrhage and tissue injury complications.

项目摘要 由血管内血凝块引起的血栓形成是这三种疾病中最常见的基础病理 主要心血管疾病：缺血性心脏病、中风和静脉血栓栓塞。的显著 高发病率及其致命后果要求寻找安全有效的溶栓药物 酶，在过去的几十年里仍然广泛存在。尽管努力，目前 血栓溶解剂具有显著的缺点，包括出血并发症。目前所有的溶栓药物 参与纤溶酶原活化为纤溶酶。不幸的是， 纤溶酶降解参与止血和伤口愈合的必需蛋白质。因此，纤溶酶的临床应用- 依赖性溶栓治疗受到限制，需要在卒中后3小时内开始治疗 以避免致命的出血并发症。对新的溶栓药物的需求仍然迫切， 无需担心出血和组织损伤并发症。 SNJ Pharma，Inc.识别出现的HtrA 1（高温要求A1，命名为凝血酶） 对血管内凝块发挥强的血栓溶解活性，同时允许正常的伤口愈合。不像所有 目前可用的溶血栓剂，HtrA 1蛋白酶不激活纤溶酶原为纤溶酶， 导致血栓溶解治疗的致命性出血并发症的蛋白酶。HtrA 1的高度特异性 酶活性能够选择性降解病理性血栓同时保留止血凝块， 消除了大出血的风险。体内鼠模型，包括伤口切除和尾部出血测定， 结果表明，与电流相比，用HtrA 1治疗的动物在伤口愈合中没有表现出损伤。 溶血栓药此外，HtrA 1给药完全溶解了尾部血栓形成小鼠的血栓 和血管内血栓的小鼠肺栓塞时，静脉给药，导致 抢救血栓栓塞。在此，在确认HtrA 1活性的特异性和有益的细胞的保存后， 止血凝块，我们的目的是评估HtrA 1蛋白酶的治疗效果及其对血栓形成的潜力。 使用体外血栓切除术模型和体内光血栓形成AIS治疗急性缺血性卒中（AIS） 模型我们成功地完成了这一建议与第一纤溶酶非依赖性溶栓酶将 本发明的HtrA 1蛋白酶作为AIS的革命性治疗候选物，而没有有限的 在没有出血和组织损伤并发症的情况下的治疗窗口。