Exosome therapy for acute stroke with large artery occlusion

外泌体治疗急性中风伴大动脉闭塞

基本信息

批准号：
10550210
负责人：
ZHENG GANG ZHANG
金额：
$ 39.53万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550210
关键词：
Acute Adjuvant Therapy Adult Alteplase Blood - brain barrier anatomy Brain hemorrhage Cell Adhesion Molecules Cells Cerebral Ischemia Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Data Development Eligibility Determination Endothelial Cells Extravasation FDA approved Genes Goals Human Infarction Intercellular adhesion molecule 1 Ischemia Ischemic Stroke Knock-out Life Lipids Mediating MicroRNAs Middle Cerebral Artery Occlusion Modeling Molecular Nervous System Physiology Neurological outcome Outcome Patients Perfusion Play Proteins RNA Rattus Reperfusion Therapy Role Signal Transduction Stroke Testing Therapeutic Therapeutic Effect Thrombectomy Thromboplastin Thrombosis Tissues Toll-like receptors Treatment Efficacy acute stroke aged artery occlusion blood-brain barrier disruption brain endothelial cell exosome experience gene network improved intercellular communication middle age nanovesicle neurovascular injury novel therapeutics standard of care success therapy development thrombogenesis thrombolysis thrombotic vascular injury

项目摘要

Abstract: Large cerebral vessel occlusion is the most disabling and life-threatening form of ischemic stroke. Human stroke primarily occurs in late middle age and beyond. Approximately two thirds eligible patients treated with tPA experience incomplete reperfusion. Thrombectomy is now also a standard of care for treatment of acute stroke with large vessel occlusion. However, recanalization of the occluded large vessels by thrombectomy only leads to ~71% of patients achieving improved tissue reperfusion, often incomplete. In addition, due to unfavorably large ischemic cores, many patients with large artery occlusion are not eligible to receive tPA or thrombectomy. Patients with reperfusion of the ischemic tissue are closely associated with good clinical outcome. Thus, there is a compelling need to develop therapies in combination with tPA and thrombectomy to enhance cerebral perfusion and thereby augment the therapeutic efficacy of tPA and thrombectomy monotherapies. Also, therapies to block ischemic core expansion will increase numbers of patients who would be eligible to receive tPA and thrombectomy. Using rat models of embolic middle cerebral artery occlusion (eMCAO) and transient MCAO (tMCAO, ischemia/reperfusion), we found that exosomes derived from cerebral endothelial cells (CEC- exos) in combination with tPA after eMCAO or CEC-exos given upon reperfusion after tMCAO substantially increased recanalization and downstream cerebral blood flow (CBF), and reduced blood brain barrier (BBB) leakage and infarction compared to tPA or tMCAO alone. Exosomes are nano-vesicles that contain lipids, proteins, and RNAs including microRNAs (miRs). Our preliminary data suggest that exosomal cargo miRs likely contribute to the therapeutic effect of CEC-exos in combination with tPA on acute stroke by acting on cerebral endothelial cells to suppress proteins that promote thrombosis and BBB disruption. We thus propose to develop CEC-exo therapy as an adjunctive treatment to enhance tPA and thrombectomy treatments of acute ischemic stroke. Aim 1 is to investigate whether the CEC-exo therapy as an adjunctive treatment enhances tPA and thrombectomy treatments in aged rats after large artery occlusion. Aim 2 is to investigate whether CEC exosomal cargo miRs contribute to CEC-exos-amplified thrombolysis leading to reduction of neurovascular damage. Aim 3 investigates whether a special set of CEC-exo cargo miRs contribute to the therapeutic effect CEC-exos on stroke- induced neurovascular damage by suppressing a network of pro-BBB leakage and thrombotic genes. Accomplishing these aims will potentially lead to development of a mechanistically based exosome therapy as an adjunctive treatment to enhance tPA and thrombectomy treatments of acute ischemic stroke, leading to improvement in the neurological outcome.

抽象的：大脑血管闭塞是缺血性中风中最严重的致残和危及生命的形式。人类中风主要发生在中年后期及以后。大约三分之二符合条件的患者接受tPA治疗的患者经历了不完全再灌注。血栓切除术现在也是治疗的标准治疗伴有大血管闭塞的急性中风。然而，闭塞大血管的再通通过血栓切除术只能使约 71% 的患者实现组织再灌注的改善，但通常是不完全的。在此外，由于缺血核心不利，许多大动脉闭塞的患者不适合接受接受 tPA 或血栓切除术。患者缺血组织再灌注与以下因素密切相关：良好的临床效果。因此，迫切需要开发与 tPA 和血栓切除术可增强脑灌注，从而增强 tPA 和血栓切除术单一疗法。此外，阻止缺血性核心扩张的疗法将增加有资格接受 tPA 和血栓切除术的患者。大鼠中脑栓塞模型的建立动脉闭塞（eMCAO）和短暂性 MCAO（tMCAO，缺血/再灌注），我们发现外泌体源自脑内皮细胞 (CEC-exos) 与 eMCAO 或 CEC-exos 后的 tPA 组合 tMCAO 后再灌注显着增加再通和下游脑血与单独使用 tPA 或 tMCAO 相比，血流 (CBF) 减少，血脑屏障 (BBB) 渗漏和梗塞减少。外泌体是含有脂质、蛋白质和 RNA（包括 microRNA (miR)）的纳米囊泡。我们的初步数据表明，外泌体货物 miR 可能有助于 CEC-exos 的治疗效果与 tPA 联合治疗急性中风，通过作用于脑内皮细胞抑制蛋白质促进血栓形成和血脑屏障破坏。因此，我们建议开发 CEC-exo 疗法作为辅助疗法治疗以加强急性缺血性中风的 tPA 和血栓切除术治疗。目标 1 是调查 CEC-exo 疗法作为辅助治疗是否可以增强 tPA 和血栓切除术治疗大动脉闭塞后的老年大鼠。目标 2 是研究 CEC 外泌体货物 miR 是否有助于 CEC-exos 放大溶栓，从而减少神经血管损伤。目标 3 研究一组特殊的 CEC-exo 货物 miR 是否有助于 CEC-exo 对通过抑制亲 BBB 渗漏和血栓基因网络，中风引起的神经血管损伤。实现这些目标将有可能导致基于机械的外泌体的开发治疗作为辅助治疗，以增强急性缺血性中风的 tPA 和血栓切除术治疗，从而改善神经系统结果。