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

描述（由申请人提供）：乔治亚医学院脑与行为发现研究所，在开发新的中风治疗药物项目的背景下，提交了一项名为“Mini-plasmin：一种新的中风溶栓策略的临床前评估”的创新研究计划。这个项目的目的是开发一种新颖的、可替代的、但高风险的急性中风治疗方法。它代表了一个独特的翻译分子见解到中风的临床前模型和范式转变，如何溶栓在中风可能接近。中风是美国第三大死亡原因，也是成年人致残的主要原因。随着人口的老龄化，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，重组组织型纤溶酶原激活剂（TPA）被FDA批准用于治疗缺血性中风。然而，人们对TPA的安全性有很大的担忧。此外，TPA往往是无效的。由于这些担忧，TPA仅用于2%的缺血性中风患者。TPA在实现高效、安全再灌注方面的高失败率导致制药行业和神经血管研究放弃了缺血性脑卒中作为靶标疾病的研究。显然，需要更有效和更安全的代理以及更有创造性的方法。缺血性中风的基本机制是富含纤维蛋白的血凝块（血栓）阻塞脑血管。我们的目标是设计一种新的脑动脉直接再通的溶栓剂，它不通过不同的途径独立于溶栓。这些研究将首次表征迷你纤溶蛋白结构对脑卒中溶栓的影响，并将作为进一步评估具有理想性能的新型嵌合纤溶蛋白的先导数据。主要的想法是证明有效溶栓的可行性，该药物可以协同结合1)纤维蛋白靶向，2)直接的纤维蛋白溶解活性和3)中和全身纤溶酶抑制剂的后续能力。我们建议在体外和体内模型中测试微型纤溶酶分子。我们认为，与TPA相比，迷你纤溶酶可能具有更高的再通率、更低的出血率和更高的神经保护作用。我们已经组建了一个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方面的专家组成的团队来解决这个问题。该项目涉及急性脑卒中治疗领域的一个核心问题，我们相信改进的溶栓治疗和缺血性脑卒中的结果应该直接转化为降低死亡率和发病率。

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.