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

描述（由申请方提供）：重组tPA静脉给药仍然是卒中急诊治疗中最有益的经证实的干预措施。然而，低再灌注率，短的治疗时间窗，出血性转化和神经毒性的并发症构成了tPA临床上的主要局限性。在本申请中，我们提出了一个翻译计划，开发重组膜联蛋白A2蛋白（rA 2）加低剂量tPA作为急性缺血性卒中的联合溶栓治疗。我们有8个具体的目标，从控制良好的大鼠栓塞性中风模型的实验到IND准备的临床前研究，并在我们的5年项目结束时提交。 1.大鼠局灶性栓塞性卒中模型中rA 2联合低剂量tPA的剂量范围研究 2.确定最佳rA 2加低剂量tPA组合对长期神经结局的影响。 3.量化再通/再灌注疗效，并在第二个研究中心复制神经保护。 4.确定rA 2加低剂量tPA的治疗时间窗。 5.检查rA 2-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rA 2-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rA 2加低剂量tPA作为潜在卒中治疗药物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rA 2 + tPA最佳联合剂量的IND申请。 在本U 01中，我们正在开发一种基于经证实的方法（即溶栓和再灌注）的药物。我们所要做的就是让tPA更好地发挥作用。我们的目标很明确。我们的里程碑是基于量化的“去-不去”标准。为了临床相关，药物必须改善长期神经功能。它必须像预期的那样再通。它必须不仅对健康的年轻雄性动物有效，而且对雌性动物和具有中风风险因素（高血压、老年）的动物也有效。一定很安全。当然，最重要的是，它必须优于标准tPA剂量。我们的试验数据很有希望。我们的终点和里程碑与临床试验中将追求的内容直接相关，即神经学结局和成像。如果成功的话，这种转化UOI程序可能会为我们带来一种强大的中风治疗新方法。

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.