Mini-plasmin: Pre-Clinical Evaluation of a Novel Thrombolytic Strategy for Stroke

微型纤溶酶：中风新型溶栓策略的临床前评估

• 批准号: 8032016
• 负责人: Irina Y. Sazonova
• 金额: $ 21.96万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032016
• 关键词: Acute; Adult; Adverse effects; Affect; Alteplase; Antiplasmin; Arteries; Behavior; Benefits and Risks; Biochemical; Biological Assay; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Brain; C-reactive protein; Cause of Death; Cerebral Edema; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrum; Characteristics; Chimera organism; Clinical; Clinical Trials; Coagulation Process; Comparative Study; Consumption; Cytolysis; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Industry; Edema; Evaluation; FDA approved; Failure; Fibrin; Fibrin split products; Fibrinogen; Fibrinolytic Agents; Foundations; Gelatinase A; Gelatinase B; Goals; Healthcare; Hemorrhage; Hemostatic Agents; Human; In Vitro; Incidence; Infarction; Inflammatory; Institutes; Investigational Drugs; Ischemic Stroke; Measures; Metalloproteases; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; New Agents; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Plasmin; Plasmin Inhibitor; Plasminogen; Pre-Clinical Model; Program Development; Property; Proteins; Recombinants; Reperfusion Therapy; Research; Research Personnel; Research Proposals; Risk; Risk Estimate; Safety; Simulate; Stroke; Stromelysin 1; Structure; Supplementation; System; Testing; Therapeutic; Therapeutic Agents; Thrombolytic Therapy; Thrombus; Time; Tissue Inhibitor of Metalloproteinase-1; Translating; Translations; Treatment Efficacy; acute stroke; aging population; base; brain behavior; comparative; design; disability; effective therapy; experience; high risk; improved; in vivo Model; innovation; insight; intravenous administration; medical schools; middle cerebral artery; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; pre-clinical research; primary outcome; research clinical testing; restoration; simulation; stroke therapy; therapy outcome; thrombolysis; tool

DESCRIPTION (provided by applicant): The Brain and Behavior Discovery Institute of the Medical College of Georgia, in the context of the program for development of new therapeutic agents for stroke, submits this Innovative Research Proposal entitled "Mini-plasmin: Pre-Clinical Evaluation of a Novel Thrombolytic Strategy for Stroke". The rational for this project is to develop a novel and alternative, but high risk approach to acute stroke. It represents a unique translation of molecular insights into pre- clinical model of stroke and a paradigm shift in to how thrombolysis in stroke may be approached. Stroke is the third leading cause of death in the U.S. and the leading cause of disability amongst adults. With the aging population, the incidence of stroke is expected to rise. Despite the testing of over 70 agents in clinical trials, only one drug, the recombinant tissue plasminogen activator (TPA), has been approved by the FDA for the treatment of ischemic stroke. However, there are major concerns regarding the safety of TPA. Moreover, TPA is often ineffective. Due to those concerns, TPA is used on only 2% of ischemic stroke patients. The high failure of TPA to achieve efficient and safe reperfusion has led to the abandonment of ischemic stroke as a target disease by the pharmaceutical industry and neurovascular research. Clearly, more effective and safer agents along with more creative approaches are required. The fundamental mechanism of ischemic stroke is the occlusion of a cerebral vessel by a fibrin rich blood clot (thrombus). We aim to elaborate a novel thrombolytic agent for direct recanalization of brain arteries, which is not involved via different pathways independent of thrombolysis. These studies will characterize for the first time the effect of mini-plasmin structure on thrombolysis of stroke and will serve as a pilot data for further evaluation of a novel chimeric plasmin with desirable properties. The main idea is to demonstrate the feasibility of efficient thrombolysis by the agent that can synergistically combine 1) the fibrin targeting, 2) the direct fibrinolytic activity and 3) the following ability to neutralize systemic plasmin inhibitor. We propose to test mini-plasmin molecule in both in vitro and in vivo models. We believe that mini- plasmin may achieve high recanalization rates, lower hemorrhage rates, and higher neuro- protection than TPA. We have assembled a team of experienced basic and clinical stroke researchers and experts in pharmacology and drug delivery to approach the problem. This project deals with a central problem in the field of acute stroke therapy, and we believe that improved thrombolytic therapy and outcomes for ischemic stroke should be directly translated into reduced mortality and morbidity. PUBLIC HEALTH RELEVANCE: Project Narrative Ischemic stroke is a major health and socio-economic problem, affecting many individuals. Relevant to this reality, investigators in stroke research are looking into efficient and safe thrombolytic therapy to improve the recovery from stroke. In this project we propose a novel thrombolytic agent and plan to determine its efficacy for the treatment in an experimental model of thromboembolic cerebral ischemia.

描述（由申请人提供）：佐治亚州医学院的大脑和行为发现研究所，在开发新的中风治疗剂计划的背景下，提交了这项题为“微型质蛋白：中风的新型血栓溶液策略的临时评估”的创新研究建议。该项目的理性是开发一种新颖而替代的急性中风风险方法。它代表了分子洞察到中风前临床模型的独特翻译，以及向中风中溶栓的范式转变。中风是美国第三大死亡原因，也是成年人残疾的主要原因。随着人口老龄化，中风的发生率预计将上升。尽管在临床试验中测试了70多种药物，但仅FDA批准了一种药物，即重组组织纤溶酶原激活剂（TPA），用于治疗缺血性中风。但是，关于TPA的安全存在主要问题。此外，TPA通常无效。由于这些担忧，只有2％的缺血性中风患者使用TPA。 TPA无法实现高效且安全的再灌注，导致制药行业和神经血管研究放弃了缺血性中风作为靶向疾病。显然，需要更有效，更安全的代理以及更具创意的方法。缺血性中风的基本机制是通过富含纤维蛋白的血凝块（血栓）阻塞大脑血管。我们旨在阐述一种新型的溶栓剂，以直接重新加续脑动脉，这与独立于溶栓无关的不同途径不参与。这些研究将首次表征微量质蛋白结构对中风的溶栓的影响，并将作为试点数据，以进一步评估具有理想特性的新型嵌合纤溶酶。主要思想是证明可以协同结合纤维蛋白靶向的药物有效溶栓的可行性，2）直接纤维蛋白溶解活性和3）以下能力中和中和全身性纤溶酶抑制剂。我们建议在体外和体内模型中测试微质蛋白分子。我们认为，与TPA相比，迷你纤溶酶可能达到高回收率，较低的出血率和更高的神经保护。我们组建了一支由经验丰富的基础和临床中风研究人员以及药理学和药物输送专家的团队，以解决该问题。该项目涉及急性中风疗法领域中的一个核心问题，我们认为改善了溶栓疗法和缺血性中风的结果应直接转化为死亡率和发病率的降低。 公共卫生相关性：项目叙事缺血性中风是一个主要的健康和社会经济问题，影响了许多人。与这一现实相关的是，中风研究的研究人员正在研究有效且安全的溶栓疗法，以改善中风的恢复。在这个项目中，我们提出了一种新型的溶栓剂，并计划在血栓栓塞脑缺血的实验模型中确定其治疗的功效。