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.

主要研究者/项目负责人（最后，第一，中间：Soon Seog Jeong 摘要 由于其给药时间窗较窄（症状后最多4.5小时），风险增加6-7倍 在颅内出血中，只有3-5%的急性缺血性卒中患者接受重组组织 纤溶酶原激活剂（tPA）是FDA批准的唯一用于该适应症的药物。神经生长因子预防神经元凋亡 在原代培养的神经元中， 疾病在中枢神经系统中，NGF在整个成人生活中产生，并且主要针对基底神经系统。 前脑和纹状体神经元。已经表明，鼻内（IN）NGF绕过血脑屏障， 分布于全脑，无外周副作用。IN施用野生型NGF显著地 通过保护神经元免受缺血性损伤减少梗死体积和改善神经学结果， 促进血管生成，并在卒中后至少24小时的治疗窗内增强纹状体神经发生 发病 我们已经优化了人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。这种专利变体选择性激活NGF TrkA受体，活性增强 来促进神经元的存活和功能在一项大鼠随机盲法研究中， 血栓栓塞性卒中后6小时（rt-PA治疗时间窗外）持续3周， 卒中后28天评估的短期和长期神经功能缺损评分改善。在这项研究中，我们将 遵循STAIR建议和RIGOR指南进行I期临床前研究，以验证 在使用雄性和雌性动物的中风大鼠模型中使用tPA的组合治疗。长期 我们的目标是开发dug候选药物作为急性或亚急性治疗，单独或与tPA联合， 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变体组合是否更有效地改善 在血栓栓塞性卒中大鼠模型中，与溶媒和tPA相比， 缺血6 h。