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

基本信息

批准号：
8215615
负责人：
ALEXANDER D VERIN
金额：
$ 18.7万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215615
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 Experimental Models FDA approved Failure Fibrin Fibrin split products Fibrinogen Fibrinolytic Agents Foundations Gelatinase A Gelatinase B Goals Health Healthcare Hemorrhage Hemostatic Agents Human In Vitro Incidence Individual 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 public health relevance research clinical testing restoration simulation socioeconomics stroke recovery stroke therapy therapy outcome thrombolysis tool

项目摘要

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）：佐治亚医学院大脑与行为发现研究所在中风新治疗药物开发计划的背景下，提交了题为“微型纤溶酶：临床前评估”的创新研究提案中风新型溶栓策略的研究”。该项目的目的是开发一种新颖的替代性但高风险的治疗急性中风的方法。它代表了分子见解对中风临床前模型的独特转化，以及如何进行中风溶栓的范式转变。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，中风的发病率预计会上升。尽管在临床试验中测试了 70 多种药物，但只有一种药物，重组组织纤溶酶原激活剂 (TPA)，已被 FDA 批准用于治疗缺血性中风。然而，人们对 TPA 的安全性存在重大担忧。此外，TPA 常常无效。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、安全的再灌注，导致制药行业和神经血管研究放弃缺血性中风作为目标疾病。显然，需要更有效、更安全的药物以及更具创造性的方法。缺血性中风的基本机制是脑血管被富含纤维蛋白的血凝块（血栓）阻塞。我们的目标是研制一种新型溶栓剂，用于直接使脑动脉再通，不通过独立于溶栓的不同途径参与。这些研究将首次表征微型纤溶酶结构对中风溶栓的影响，并将作为进一步评估具有理想特性的新型嵌合纤溶酶的试点数据。主要思想是证明通过能够协同结合 1) 纤维蛋白靶向、2) 直接纤溶活性和 3) 中和全身纤溶酶抑制剂的能力的药物进行有效溶栓的可行性。我们建议在体外和体内模型中测试微型纤溶酶分子。我们相信，与 TPA 相比，微型纤溶酶可以实现高再通率、更低的出血率和更高的神经保护作用。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组成的团队来解决这个问题。该项目解决了急性中风治疗领域的一个核心问题，我们认为改善缺血性中风的溶栓治疗和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：项目叙述缺血性中风是一个重大的健康和社会经济问题，影响着许多人。与这一现实相关，中风研究的研究者正在寻找有效且安全的溶栓疗法，以改善中风的康复。在这个项目中，我们提出了一种新型溶栓剂，并计划在血栓栓塞性脑缺血实验模型中确定其治疗效果。