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

描述(由申请人提供)：佐治亚医学院大脑和行为发现研究所，在开发新的中风治疗药物计划的背景下，提交了这项创新的研究提案，题为“Mini-纤溶酶：一种新的中风溶栓策略的临床前评估”。这个项目的合理性是开发一种新的、可替代的、但高风险的治疗急性中风的方法。它代表了分子洞察力到中风临床前模型的独特转换，以及如何在中风中进行溶栓治疗的范式转变。中风是美国第三大致死原因，也是成年人致残的主要原因。随着人口老龄化，中风的发病率预计将上升。尽管有70多种药物在临床试验中进行了测试，但只有一种药物--重组组织型纤溶酶原激活剂(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在实现有效和安全再通方面的高度失败率已导致制药行业和神经血管研究放弃了将缺血性卒中作为靶向疾病。显然，需要更有效、更安全的代理人以及更具创造性的方法。缺血性中风的基本机制是富含纤维蛋白的血液凝块(血栓)阻塞脑血管。我们的目标是开发一种新的溶栓剂，用于脑动脉的直接再通，它不涉及独立于溶栓的不同途径。这些研究将首次表征微小纤溶酶结构在卒中溶栓治疗中的作用，并将作为进一步评估具有理想特性的新型嵌合纤溶酶的先导数据。其主要思想是证明这种药物能够协同结合1)纤维蛋白靶向性、2)直接纤溶活性和3)以下中和全身纤溶酶抑制物的能力来进行有效的溶栓的可行性。我们建议在体外和体内模型中测试微小纤溶酶分子。我们认为，与TPA相比，迷你纤溶酶可以获得更高的再通率、更低的出血率和更高的神经保护。我们已经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方面的专家组成的团队来解决这个问题。该项目涉及急性卒中治疗领域的一个中心问题，我们认为，改善缺血性卒中的溶栓治疗和结果应该直接转化为降低死亡率和发病率。 公共卫生相关性：项目叙述缺血性中风是一个主要的健康和社会经济问题，影响到许多人。与这一现实相关的是，中风研究的研究人员正在寻找有效和安全的溶栓疗法，以促进中风的康复。在这个项目中，我们提出了一种新的溶栓剂，并计划在血栓栓塞性脑缺血的实验模型中确定其治疗效果。

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.