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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(倒数第一中：郑洵锡