Novel Neuroprotective/Restorative Therapy for Ischemic Stroke

缺血性中风的新型神经保护/恢复疗法

• 批准号: 8314513
• 负责人: David E Smith
• 金额: $ 119.43万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314513
• 关键词: Address; Adenovirus Protein; Affect; Age; Animal Model; Area; Blood - brain barrier anatomy; Blood flow; Caring; Cause of Death; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Clinic; Clinical; Clinical Trials; Cognitive; Comorbidity; Controlled Study; Data; Diabetes Mellitus; Dose; Event; Female; Funding; General Hospitals; Genes; Goals; Growth; Growth Factor; Guidelines; Half-Life; Hepatocyte Growth Factor; Hippocampus (Brain); Hour; Hypertension; Hypotension; Immune response; Industry; Infarction; Inflammatory Response; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Laboratories; Living Costs; Massachusetts; Metabolic syndrome; Middle Cerebral Artery Occlusion; Modeling; Molecular Weight; Morbidity - disease rate; Motor Cortex; Mus; Nervous System Physiology; Neurons; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Preclinical Drug Development; Production; Prosencephalon; Proteins; Rattus; Recording of previous events; Research; Research Personnel; Role; Safety; Services; Small Business Innovation Research Grant; Solutions; Stroke; Stroke prevention; Testing; Therapeutic; Thrombolytic Therapy; Tissues; United States; Universities; Zucker Rats; artery occlusion; base; brain cell; cerebral artery; efficacy testing; inclusion criteria; male; meetings; mimetics; mortality; mouse model; neurotrophic factor; novel; patient population; pre-clinical; preclinical study; prevent; research study; response; small molecule; stroke therapy; synaptogenesis

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.

描述(由申请人提供)：在美国，缺血性中风仍然是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，显然还需要其他治疗策略，如神经保护剂或恢复剂。不幸的是，对治疗药物的追求仍然受到历史上失败的临床试验的困扰，这些试验涉及有前途的神经保护候选药物。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，而不是针对导致缺血性神经元损伤的级联反应中的单一途径。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，这种药物发挥直接的神经保护作用，并增加到缺血区的血流量。肝细胞生长因子(HGF)是一种神经营养因子，可缩小脑梗塞面积，增加脑血流量，促进神经发生和突触形成，尤其是在梗塞周围或半暗带区域生长成熟的功能性神经元。虽然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以及其他问题的限制，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昂贵的生产。我们已经确定BB3，一种有机的小分子HGF类似物，可以穿越血脑屏障，在暂时性和永久性大脑中动脉闭塞的大鼠模型tMCAO和pMCAO中发挥神经保护作用(即使在延迟给药时)，并增加缺血后的血流量。最近，在严格控制的研究下，我们在Angion和杜克大学David Warner博士的实验室独立确认了BB3的活性。令人兴奋的是，华纳博士的团队已经证明，在永久性和暂时性的大鼠大脑中动脉闭塞(MCAO)模型中，BB3在第28天对梗塞面积和神经功能都有显著影响，当在闭塞后6小时首次给药时。SBIR第二阶段资助下的这项研究工作已接近完成，我们希望在1999年中风治疗学术行业圆桌会议(STAIR)的指导下，进一步验证该药物作为中风潜在疗法的有效性，该圆桌会议仍然是中风神经保护和恢复性药物临床前药物开发的标准。这里提出的额外的临床前研究将满足STAIR在与马萨诸塞州综合医院(MGH)的华纳博士和森克·阿亚塔博士的合作下颁布的这些指南。在完成临床前研究后，我们建议在MGH中风服务主任Karen Furie博士的指导下，在MGH中风患者中进行一项剂量递增的安全性试验，从而进入诊所。 公共卫生相关性：在美国，缺血性中风是一个主要的死亡原因。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。BB3/Refanalyin是一种小分子的HGF模拟物，已被证明在动物模型中具有保护脑细胞的作用，并可能被证明是治疗缺血性中风的一种新疗法。