tPA and NGF therapy for stroke

tPA 和 NGF 治疗中风

基本信息

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
项目类别：
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&apos 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

项目摘要

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较窄（症状后最多 4.5 小时）且风险增加 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。在一项针对大鼠的随机盲法研究中，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）改善中风后 28 天评估的短期和长期神经功能缺损评分。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 变体相结合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。