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

• 批准号: 8541066
• 负责人: XIAOYING WANG
• 金额: --
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541066
• 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; 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

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.

描述（由申请人提供）：重组TPA的静脉注射仍然是中风紧急治疗的最有益的干预措施。但是，低再灌注率，短期治疗时间窗口以及出血转化和神经毒性的并发症包括临床上TPA的主要局限性。在此应用中，我们提出了一项转化计划，以开发重组膜联蛋白A2蛋白（RA2）和低剂量TPA作为急性缺血性中风的组合溶栓疗法。我们有8个特定的目标，从良好控制的大鼠栓塞模型的实验到在我们5年项目结束时进行IND准备和提交的临床前研究。 1。RA2的剂量范围研究与大鼠局灶性栓塞中风模型中的低剂量TPA结合。 2。确定最佳RA2和低剂量TPA组合在长期神经系统上的影响。 3。量化再融化/再灌注功效并在第二研究地点复制神经保护。 4。确定RA2和低剂量TPA的治疗时间窗口。 5。检查雌性和老化大鼠中风模型中RA2-剂量-TPA组合的功效。 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和低剂量TPA的药代动力学和毒性谱作为潜在的中风治疗。 8。根据功效，药代动力学和毒性概况提交IND应用RA2加上TPA的最佳组合剂量。 在这个U01中，我们正在基于验证的方法（即溶栓和再灌注）开发一种药物。我们要做的就是使TPA工作得更好。我们的目标很简单。我们的里程碑基于定量的GO-NO-GO标准。为了在临床上相关，该药物必须改善长期神经功能。它实际上必须像应有的那样重新启动。它不仅必须在健康的年轻男性中，而且在女性和中风风险因素（高血压，老年）的动物中起作用。它必须安全。当然，最重要的是，它必须比标准TPA剂量更好。我们的飞行员数据很有希望。我们的终点和里程碑与临床试验（即神经学结果和成像）中所追求的终点和里程碑直接相关。如果成功的话，这种翻译的UOI prgram可能会导致我们采取一种有力的中风疗法的新方法。