Novel Neuroprotective/Restorative Therapy for Ischemic Stroke

描述（由申请人提供）：缺血性卒中仍然是美国发病率和死亡率的主要原因。目前批准的溶栓疗法的治疗窗口狭窄，显然需要其他治疗策略，如神经保护剂或恢复剂。不幸的是，对治疗方法的探索仍然受到失败的临床试验的历史的困扰，这些临床试验涉及有希望的神经保护候选物。与其靶向导致缺血性神经元损伤的级联反应中的单一通路，用多功能化合物或内源性多作用因子的补充剂治疗可能是预防缺血性脑损伤的更好选择。治疗脑缺血的最令人兴奋的研究领域之一是使用血管生成生长因子，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。肝细胞生长因子（HGF）是一种神经营养因子，可缩小脑梗死面积，增加脑血流量，促进轴突发生和突触发生，即成熟的功能性神经元的生长，特别是在梗死周围区域或半影区。虽然HGF作为基因或蛋白质疗法的给药具有治疗缺血性中风的潜力，但这种方法的治疗可行性受到血脑屏障的存在以及其他问题的限制，例如腺病毒蛋白引起的免疫和炎症反应、蛋白质在溶液中的固有不稳定性、其有限的组织半衰期和成本过高的生产。我们已经确定了BB 3，一种有机小分子HGF模拟物，其穿过血脑屏障，发挥神经保护作用（即使在延迟设置中施用），并分别在暂时性和永久性大脑中动脉闭塞（tMCAO和pMCAO）的大鼠模型中增加缺血后血流。最近，在严格控制的研究中，我们在Angion并在杜克大学大卫·华纳博士的实验室中独立证实了BB 3的活性。令人兴奋的是，Warner博士的研究小组已经证明，在大鼠大脑中动脉闭塞（MCAO）的永久性和暂时性模型中，当在闭塞后6小时首次给药时，BB 3在第28天对梗死面积和神经功能都有显着影响。SBIR第二阶段资助下的这项研究工作即将完成，我们希望根据1999年卒中治疗学术行业圆桌会议（STAIR）的指导方针进一步验证该药物作为卒中的潜在治疗方法，该指南仍然是卒中神经保护和恢复药物临床前药物开发的标准。在与马萨诸塞州总医院（MGH）的Warner博士和Cenk Ayata博士的合作下，此处拟定的其他临床前研究将满足STAIR颁布的这些指南。在完成临床前研究后，我们建议与MGH卒中服务主任Karen Furie博士一起在MGH的卒中患者中进行剂量递增的安全性试验。 公共卫生相关性：缺血性中风是美国的主要死亡原因。不幸的是，寻找新的神经保护疗法的尝试在临床试验中惨败。BB 3/Refanalin是一种小分子量的HGF模拟物，在动物模型中显示出对脑细胞的保护作用，并可能被证明是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 multi-role 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. Hepatocyte growth factor (HGF) a neurotrophic factor, reduces cerebral infarct size, augments cerebral blood flow and promotes neuritogenesis and synaptogenesis, the growth of mature, functional neurons specifically in the peri-infarct region or penumbra. While administration of 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 BB3, an organic small-molecule HGF mimetic that crosses the blood brain barrier, exerts neuroprotective effects (even when administered in a delayed setting) and augments post ischemic blood flow in rat models of temporary and permanent mid-cerebral artery occlusion, tMCAO and pMCAO, respectively. More recently under rigorously controlled studies, we have confirmed the activity of BB3 at Angion and independently in the laboratory of Dr. David Warner, Duke University. Excitingly, Dr Warner's group has demonstrated a significant effect of BB3 both on infarct size and neurologic function at day 28 in both permanent and temporary models of mid-cerebral artery occlusion (MCAO) in the rat, when first dosed 6 hours after occlusion. This research effort under SBIR phase II funding is near completion and we look to further validate the drug as potential therapy for stroke under the guideline 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. The additional pre-clinical studies proposed here will satisfy these guidelines as promulgated by STAIR under a collaborative effort with Dr. Warner and Dr. Cenk Ayata of Massachusetts General Hospital (MGH). Upon completion of the pre-clinical studies, we propose to enter the clinic by conducting a dose-escalating safety trial in stroke patients at MGH with Dr Karen Furie, Director MGH Stroke Services. 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. BB3/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.