tPA and NGF therapy for stroke

tPA 和 NGF 治疗中风

• 批准号: 10251710
• 负责人: Soon Seog Jeong
• 金额: $ 35.95万
• 依托单位: HUMAN CELL CO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251710
• 关键词: Acute; Address; Adult; Adverse effects; Alteplase; Alzheimer' s disease model; Animal Model; Animals; Apoptosis; Attenuated; Binding; Biodistribution; Blinded; Blood - brain barrier anatomy; Brain; Bypass; Cell Density; Cell Line; Cells; Chemicals; Cleaved cell; Clinical; Clinical Trials; Clone Cells; Complication; Corpus striatum structure; Data; Disabled Persons; Edema; Enzymes; Escherichia coli; Exhibits; Eyedrops; FDA approved; Female; Glaucoma; Goals; Growth; Guidelines; Hour; Human; Infarction; Injury; Intracranial Hemorrhages; Intranasal Administration; Investigational New Drug Application; Ischemic Stroke; Life; Mediating; Memory impairment; Modeling; Modification; Mus; Nerve Degeneration; Nerve Growth Factors; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurologic Deficit; Neurological outcome; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Outcome; Patients; Peptide Signal Sequences; Peripheral; Pharmaceutical Preparations; Phase; Principal Investigator; Process; Production; Proteins; Randomized; Rattus; Receptor Signaling; Recommendation; Recovery; Retinal Ganglion Cells; Risk; Safety; Serum; Signal Transduction; Stroke; Suspensions; Symptoms; Synaptic plasticity; System; Technology; Therapeutic; Time; Toxic effect; Traumatic Brain Injury; Trypsin; Validation; Variant; Work; aged; analog; angiogenesis; aquaporin 4; basal forebrain; brain tissue; clinically relevant; comorbidity; cost effective; disability; expression vector; improved; innovation; ischemic injury; male; mutant; neurogenesis; neuron apoptosis; neurovascular; post stroke; post stroke depression; pre-clinical; preclinical study; preservation; prevent; programs; promoter; stroke model; stroke outcome; stroke patient; stroke recovery; stroke therapy; thromboembolic stroke

Principal Investigator/Program Director (Last, First, Middle: Soon Seog Jeong Abstract Due to its narrow time-window of administration (up to 4.5 hours post symptoms) and 6-7 fold increased risk of intracranial hemorrhage, merely 3-5% of acute ischemic stroke patients receive recombinant tissue plasminogen activator (tPA), the only FDA-approved drug for this indication. NGF prevents neuronal apoptosis in primary cultured neurons and reduces neuronal degeneration in animal models of neurodegenerative diseases. In the central nervous system, NGF is produced throughout adult life and primarily targets basal forebrain and striatal neurons. It has been shown that intranasal (IN) NGF bypassed the blood-brain barrier and distributed in the whole brain without peripheral adverse effects. IN administration of wildtype NGF significantly reduced infarct volume and improved neurological outcomes by protecting neurons from ischemic injury, promoting angiogenesis, and enhancing striatal neurogenesis with at least a 24h treatment window after stroke onset. We have optimized a human NGF variant and developed a cost-effective protein production system for making the variant. This proprietary variant selectively activates the NGF TrkA receptor with enhanced activity to promote neuron survival and function. In a randomized and blinded study in rats, IN treatment with the variant for 3 weeks 6h after thrombo-embolic stroke (outside the therapeutic treatment time window for rt-PA) robustly improved short- and long-term neurological deficit score as assessed 28 days after stroke. In this study, we will follow the STAIR recommendations and RIGOR guidelines to conduct a Phase I preclinical study to validate the the combination treatment with tPA in a rat model of stroke using both male and female animals. The long-term goal is to develop the dug candidate as acute or sub-acute therapy, alone or in combination with tPA, to safely reduce disability for millions of stroke patients. Specific Aim. Determine whether combining tPA with the proprietary NGF variant more effectively improves long-term outcomes compared to vehicle and tPA in a rat model of thrombo-embolic stroke when administered at 6h after occlusion.

首席调查员/项目主任(最后、第一、中间：Soon Seog Jeong 摘要 由于给药时间窗口较窄(出现症状后长达4.5小时)，风险增加6-7倍 在颅内出血中，只有3-5%的急性缺血性中风患者接受重组组织 纤溶酶原激活剂(TPA)，FDA批准的唯一一种用于这一适应症的药物。神经生长因子阻止神经细胞凋亡 减少神经变性动物模型中神经元的变性 疾病。在中枢神经系统中，NGF在整个成年生活中都会产生，主要针对基底细胞 前脑和纹状体神经元。已有研究表明，鼻腔内NGF绕过血脑屏障， 分布于全脑，无外周不良反应。在野生型NGF的给药方面 通过保护神经元免受缺血损伤，缩小脑梗塞体积并改善神经预后， 卒中后至少24小时治疗窗促进血管生成和促进纹状体神经再生 开始了。 我们已经优化了一种人类神经生长因子变异体，并开发了一种经济高效的蛋白质生产系统 制造变种。这种专有的变体选择性地激活NGF TrkA受体，活性增强 以促进神经元的存活和功能。在一项随机、盲法的大鼠研究中，用该变体治疗 血栓栓塞性卒中后3周6小时(rt-PA治疗时间窗外) 改善了中风后28天评估的短期和长期神经功能缺陷评分。在这项研究中，我们将 遵循阶梯建议和严格指南进行I期临床前研究，以验证 用tPA联合治疗雄性和雌性动物建立的大鼠中风模型。长期的 目标是开发DUG候选方案作为急性或亚急性疗法，单独或与tPA联合使用，以安全 减少数百万中风患者的残疾。 明确目标。确定将tPA与专有的NGF变体相结合是否会更有效地改善 在血栓栓塞性卒中大鼠模型中应用Vehicle和tPA的长期结果比较 在阻断后6h。