Novel Neuroprotective/Restorative Therapy for Ischemic Stroke

描述（由申请人提供）：缺血性中风仍然是美国发病率和死亡率的主要原因。目前批准的溶栓治疗的治疗窗口很窄，显然需要其他治疗策略，如神经保护或恢复性药物。不幸的是，对治疗方法的探索仍然受到历史上失败的临床试验的困扰，这些试验涉及有希望的神经保护候选者。与针对导致缺血性神经元损伤的级联中的单一途径相比，使用多功能化合物或补充内源性多作用因子可能是预防缺血性脑损伤的更好选择。治疗脑缺血最令人兴奋的研究领域之一是血管生成生长因子的使用，这些因子发挥直接的神经保护作用并增加缺血区域的血流量。散点因子/肝细胞生长因子（SF/HGF）神经营养，减少脑梗死面积，增加脑血流量，促进神经发生和突触发生，成熟的，功能性神经元的生长，特别是在每梗死区或半暗区。在长期啮齿类动物研究中，即使在缺血损伤开始7天后给予HGF，这些细胞效应也会导致记忆和学习能力的改善。虽然将SF/HGF作为基因或蛋白质疗法治疗缺血性卒中具有潜力，但这种方法的治疗可行性受到血脑屏障的存在、腺病毒蛋白引起的免疫和炎症反应、溶液中蛋白质固有的不稳定性、它们有限的组织半衰期和成本高昂的生产等其他问题的限制。我们已经确定了reanalin，一种有机小分子SF/HGF模拟物，可以穿过血脑屏障，发挥神经保护作用（即使在延迟设置下给药），并分别在临时和永久性大脑中动脉闭塞（tMCAO和pMCAO）大鼠模型中增加psot缺血血流量。这项研究是Angion Biomedica公司和杜克大学David Warner博士的合作协议，旨在严格独立地测试reanalin在短期和长期tMCAO和pMCAO大鼠模型中的剂量、治疗窗口和治疗持续时间，并解决老年动物的性别差异和活动。这项积极的研究计划将满足1999年卒中治疗学术产业圆桌会议（STAIR）的大部分建议，该会议仍然是卒中神经保护和恢复性药物临床前药物开发的标准。随着reanalin在我们的研究中预期的积极结果，Angion将准备完成临床前开发，包括在向FDA提交IND包装之前在非人类灵长类动物模型中测试reanalin。公共卫生相关性：缺血性中风是美国死亡的主要原因。不幸的是，寻找新的神经保护疗法的尝试在临床试验中惨遭失败。reanalin是一种小分子量的HGF模拟物，已在动物模型中显示出对脑细胞的保护作用，可能被证明是一种治疗缺血性中风的新疗法。

DESCRIPTION (provided by applicant): Ischemic Stroke continues to be a major cause of morbidity and mortality in the United States. Currently approved thrombolytic therapy suffers for a narrow therapeutic window and clearly other therapeutic strategies are needed, such as neuroprotective or restorative agents. Unfortunately the quest for a therapeutic remains beset by a history of failed clinical trials involving promising neuroprotective candidates. Instead of targeting a single pathway in the cascade leading to ischemic neuronal damage, treatment with multifunctional compounds or supplements of endogenous multirole factors might be better choices for preventing ischemic brain injury. One of the most exciting areas of research for treatment of cerebral ischemia is the use of angiogenic growth factors, agents that exert direct neuroprotective effects and augment blood flow to the ischemic region. Scatter factor/hepatocyte growth factor (SF/HGF) neurotrophic, reduces cerebral infarct size, augments cerebral blood flow and promotes neuritogenesis and synaptogenesis, the growth of mature, functional neurons specifically in the per-infarct region or penumbra. These cellular effects lead to improved memory and learning in long term rodent studies even when HGF is given 7 days after the start of the ischemic insult. While administration of SF/HGF as gene or protein therapy has potential for the treatment of ischemic stroke, the therapeutic feasibility of this approach is limited by the presence of the blood-brain-barrier, and other issues such as immune and inflammatory responses evoked by adenovirus proteins, inherent instability of proteins in solution, their limited tissue half-life and cost-prohibitive production. We have identified Refanalin, an organic small-molecule SF/HGF mimetic that crosses the blood brain barrier , exerts neuroprotective effects (even when administered in a delayed setting) and augments psot ischemic blood flow in rat models of temporary and permanent mid-cerebral artery occlusion, tMCAO and pMCAO, respectively. This research effort is a collaborative agreement between Angion Biomedica Corp. and Dr. David Warner of Duke University to rigorously and independently test the dose, therapeutic window, and therapeutic duration of Refanalin in short and long term rat models of tMCAO and pMCAO, and addressing gender differences and activity in aged animals. This aggressive research plan will meet most of the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) of 1999, which still remains the standard for preclinical drug development for stroke neuroprotective and restorative drugs. With the anticipated, positive outcome for Refanalin in our studies, Angion will be prepared to complete preclinical development, including testing Refanalin in non-human primate models before approaching the FDA with an IND package. PUBLIC HEALTH RELEVANCE: Ischemic stroke is a major cause of death in the United States. Unfortunately attempts at finding new neuroprotective therapies have failed miserably in clinical trials. Refanalin, a small molecular weight mimetic of HGF has been shown to protect brain cells in animal models and may prove to be a novel therapy to treat ischemic stroke.