Development of annexin A2 plus tPA as a novel stroke thrombolytic therapy

开发膜联蛋白 A2 加 tPA 作为新型中风溶栓疗法

基本信息

批准号：
8193720
负责人：
XIAOYING WANG
金额：
$ 85.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2011-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193720
关键词：
ANXA2 gene Acute Adhesives Adverse effects Agreement Angiography Animals Brain Brain Infarction Cerebral hemisphere hemorrhage Clinical Trials Coagulation Process Combined Modality Therapy Core-Binding Factor Data Development Dose Drug Combinations Drug Kinetics Emergency treatment Evolution Excision FDA approved Female Goals Hematoxylin and Eosin Staining Method Hemorrhage Hypertension Image Inbred SHR Rats Infarction Injection of therapeutic agent Intervention Ischemic Stroke Lead Lytic Magnetic Resonance Imaging Maps Measures Methods Modeling Motor Nervous System Physiology Neurologic Neurological outcome Outcome Perfusion Pharmaceutical Preparations Preparation Principal Investigator Proteins Publishing Rattus Recombinants Reperfusion Therapy Reproducibility Research Risk Risk Factors Saline Severities Site Streptozocin Stroke Swelling Testing Therapeutic Therapeutic Effect Thrombolytic Therapy Time Toxic effect Treatment Efficacy Work aged base clinically relevant diabetic rat foot improved intravenous administration male mortality neurobehavioral test neuroprotection neurotoxicity novel novel strategies post stroke pre-clinical preclinical study programs research study stroke therapy thrombolysis

项目摘要

DESCRIPTION (provided by applicant): Intravenous administration of recombinant tPA remains the most beneficial proven intervention for emergency treatment of stroke. However, low reperfusion rates, short treatment time windows, and complications of hemorrhagic transformation and neurotoxicity comprise the major limitations for tPA clinically. In this application, we propose a translational plan to develop recombinant Annexin A2 protein (rA2) plus low-dose tPA as a combination thrombolytic therapy for acute ischemic stroke. We have 8 specific aims going from experiments in well-controlled rat embolic stroke models to preclinical studies for IND preparation and submission at the end of our 5-year project. 1. Dose-ranging studies for rA2 combined with low-dose tPA in a rat focal embolic stroke model. 2. Determine effects of optimal rA2 plus low-dose tPA combination in long term neurological outcomes. 3. Quantify recanalization/reperfusion efficacy and replicate neuroprotection in 2nd research site. 4. Determine the therapeutic time window of rA2 plus low-dose tPA. 5. Examine efficacy of rA2-low-dose-tPA combination in female and aged rat stroke models. 6. Examine efficacy of rA2-low-dose-tPA combination in hypertensive and diabetic rat stroke models. 7. Determine pharmacokinetic and toxicity profiles of rA2 plus low-dose tPA as a potential stroke therapeutic. 8. Submit IND application for the optimal combination dose of rA2 plus tPA based on efficacy, pharmacokinetic and toxicity profiles. In this U01, we are developing a drug based on a proven approach, i.e. thrombolysis and reperfusion. All we seek to do is to make tPA work better. Our goals are straightforward. Our milestones are based on quantitative go-no-go criteria. To be clinically relevant, the drug must improve long-term neurological function. It must actually recanalize like it's supposed to. it must work not just in healthy young males, but also in female, and animals with stroke risk factors (hypertension, aged). It must be safe. And of course, most importantly, it must be better than the standard tPA dosing. Our pilot data are promising. Our endpoints and milestones are directly related with what will be pursued in a clinical trial, i.e. neurological outcomes and imaging. If successful, this translational UOI prgram may lead us to a powerful new approach for stroke therapy. PUBLIC HEALTH RELEVANCE: Intravenous administration of tPA is the only FDA-approved emergency treatment for ischemic stroke. But shortcomings of brain bleeding risk, low efficacy and toxic side effects limit this application. Here we propose a preclinical program to develop a novel combination therapy of annexin A2 plus tPA that may make stroke thrombolysis safer and more efficacious.

描述（由申请人提供）：重组 tPA 的静脉给药仍然是中风紧急治疗中最有益的已证实的干预措施。然而，再灌注率低、治疗时间窗短以及出血转化和神经毒性并发症是 tPA 临床的主要局限性。在本申请中，我们提出了一项转化计划，开发重组膜联蛋白 A2 蛋白 (rA2) 加低剂量 tPA 作为急性缺血性中风的联合溶栓疗法。我们有 8 个具体目标，从控制良好的大鼠栓塞性中风模型实验到 IND 准备和 5 年项目结束时提交的临床前研究。 1. 在大鼠局灶性栓塞性卒中模型中 rA2 联合低剂量 tPA 的剂量范围研究。 2. 确定最佳 rA2 加低剂量 tPA 组合对长期神经学结果的影响。 3. 量化再通/再灌注功效并在第二个研究地点复制神经保护作用。 4. 确定rA2加低剂量tPA的治疗时间窗。 5.检查rA2-低剂量-tPA组合在雌性和老年大鼠中风模型中的功效。 6.检查rA2-低剂量-tPA组合在高血压和糖尿病大鼠中风模型中的功效。 7. 确定 rA2 加低剂量 tPA 作为潜在中风治疗剂的药代动力学和毒性特征。 8. 根据疗效、药代动力学和毒性特征，提交 rA2 加 tPA 最佳组合剂量的 IND 申请。在这个 U01 中，我们正在开发一种基于经过验证的方法（即溶栓和再灌注）的药物。我们所要做的就是让 tPA 发挥更好的作用。我们的目标很简单。我们的里程碑是基于定量的“行不行”标准。为了具有临床意义，该药物必须改善长期神经功能。它实际上必须像预期的那样重新疏导。它不仅对健康的年轻雄性有效，而且对雌性和具有中风危险因素（高血压、老年）的动物也有效。它一定是安全的。当然，最重要的是，它必须优于标准 tPA 剂量。我们的试点数据很有希望。我们的终点和里程碑与临床试验的目标直接相关，即神经学结果和影像学。如果成功，这个转化性 UOI 计划可能会为我们带来一种强大的中风治疗新方法。公共卫生相关性：静脉注射 tPA 是 FDA 批准的唯一治疗缺血性中风的紧急治疗方法。但脑出血风险、疗效低、毒副作用等缺点限制了其应用。在此，我们提出了一项临床前计划，开发一种膜联蛋白 A2 加 tPA 的新型联合疗法，该疗法可能使中风溶栓更安全、更有效。