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.

首席研究员/项目总监（姓、名、中：Soon Seog Jeong 抽象的 由于其给药时间窗口很窄（症状后最多 4.5 小时），风险增加了 6-7 倍 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治疗 纤溶酶原激活剂（tPA）是 FDA 唯一批准用于该适应症的药物。 NGF 预防神经细胞凋亡 在原代培养的神经元中，减少神经退行性动物模型中的神经元变性 疾病。在中枢神经系统中，NGF 在整个成年过程中都会产生，主要针对基础神经元 前脑和纹状体神经元。研究表明，鼻内 (IN) NGF 可以绕过血脑屏障， 分布于全脑，无外周不良作用。野生型NGF的IN施用显着 通过保护神经元免受缺血性损伤，减少梗塞体积并改善神经系统结果， 中风后至少 24 小时的治疗窗口可促进血管生成并增强纹状体神经发生 发病。 我们优化了人类 NGF 变体并开发了一种具有成本效益的蛋白质生产系统 制作变体。这种专有变体选择性激活 NGF TrkA 受体，活性增强 促进神经元的存活和功能。在一项对大鼠进行的随机盲法研究中，使用该变体进行 IN 治疗 血栓栓塞性中风后持续 3 周 6 小时（在 rt-PA 的治疗时间窗之外） 中风后 28 天评估的短期和长期神经功能缺损评分得到改善。在本研究中，我们将 遵循 STAIR 建议和 RIGOR 指南进行 I 期临床前研究以验证 使用雄性和雌性动物对中风大鼠模型进行 tPA 联合治疗。长期来看 目标是开发所挖掘的候选药物作为急性或亚急性疗法，单独或与 tPA 联合使用，以安全地 减少数百万中风患者的残疾。 具体目标。确定将 tPA 与专有的 NGF 变体结合使用是否可以更有效地改善 与赋形剂和 tPA 相比，在血栓栓塞性中风大鼠模型中给药时的长期结果 闭塞后6h。