Human Neural Cell Exosomes as a therapeutic treatment for stroke

人类神经细胞外泌体作为中风的治疗方法

基本信息

批准号：
9907927
负责人：
Emily W Baker
金额：
$ 288.01万
依托单位：
ARUNA BIOMEDICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907927
关键词：
Acute Address Adverse effects Alteplase Animals Biological Blood Blood specimen Cerebrum Clinic Clinical Clinical Protocols Clinical Research Combined Modality Therapy Control Groups Development Diffusion Dose Drug Kinetics Drug or chemical Tissue Distribution Ensure Family suidae Feasibility Studies Funding Goals Hemorrhage Hour Human Image Immune response Incidence Industry Investigational Drugs Investigational New Drug Application Ischemic Stroke Kinetics Left Lesion Letters Maps Measures Mechanics Medical Meta-Analysis Modeling Mus Nervous System Physiology Neurons Outcome PET/CT scan Patients Perfusion Peripheral Pharmacology and Toxicology Phase Procedures Production Radioactive Tracers Rattus Recommendation Recovery Recovery of Function Regimen Reperfusion Therapy Research Safety Sensorimotor functions Small Business Innovation Research Grant Stem cells Stroke Sum Therapeutic Therapeutic Effect Thrombectomy Time Tissues Toxic effect Toxicology Work X-Ray Computed Tomography acute stroke aged brain tissue commercialization exosome extracellular vesicles first-in-human functional disability human study immunoregulation improved innovation mature animal meetings multimodality nerve stem cell neurorestoration phase 2 study post stroke pre-clinical preclinical study response restorative treatment safety assessment standard care standard of care stroke model stroke outcome stroke patient stroke therapy thrombolysis

项目摘要

Project Summary Cytoprotective and restorative treatments for acute ischemic stroke (AIS) is a major unmet medical need. The current standard of care for stroke patients is centered on recanalization efforts to restore cerebral perfusion through the administration of tissue plasminogen activator (tPA) or mechanical thrombectomy. However, despite a recent extension of recanalization treatment window, an estimated <10% of patients would be eligible for thrombolysis or thrombectomy, and a large proportion of victims are left with significant functional impairments even after reperfusion therapy. Furthermore, reperfusion therapy increases the incidence of hemorrhagic transformation which often worsens stroke outcome. When administered during the acute stroke phase, ArunA Bio’s neural stem cell-derived extracellular vesicle (NSC EV) product is effective in reducing lesion size, mitigating the systemic immune response, inhibiting hemorrhagic transformation, and promoting functional recovery. NSC EVs can be administered after the reperfusion therapy treatment window (>24 hours post-stroke) either alone or adjunctive to tPA and/or thrombectomy. Therefore, NSC EV have the potential to improve clinical AIS treatment paradigms by providing clinicians with an off-the-shelf, cytoprotective, and neurorestorative biologic to bolster recovery after recanalization efforts. The overall goal of this Phase II project is to support an Investigational New Drug (IND) application for NSC EV as a treatment for AIS. In order to advance the commercialization of NSC EV, the successful completion of Phase II studies will enable IND filing by conducting definitive pharmacology and toxicology studies in stroked rats. These goals will be achieved in the following three specific aims: 1) assess NSC EV tissue distribution and pharmacokinetics in a rat stroke model, 2) determine NSC EV dose response and associated toxicity in a rat stroke model, and 3) submit IND application for a NSC EV first-in-human study. In Aim 1, stroked rats will be treated with a high dose of NSC EV tagged with a radioactive tracer. Rats will undergo longitudinal PET/CT imaging and blood sampling to determine the kinetics of NSC EV tissue distribution and clearance. In Aim 2, stroked rats will be treated with either a one-dose or three-dose regimen of NSC EV at varying concentrations, and lesion size and sensorimotor function will be measured to determine dose response. Rats treated with the highest NSC EV dose will undergo clinical and histopathological analysis to determine any NSC EV-associated toxicity. In Aim 3, the key components of the IND submission including the pharmacology/toxicology studies outlined here as well as CMC and clinical protocols will finalized. The resulting IND application will be submitted to FDA, which is required for first-in-human studies and eventual commercialization.

项目概要急性缺血性中风（AIS）的细胞保护和恢复治疗是一个未满足的主要医疗需求。当前中风患者的护理标准集中于恢复脑灌注的再通努力然而，尽管如此，通过施用组织纤溶酶原激活剂（tPA）或机械血栓切除术。最近延长了再通治疗窗口，估计<10%的患者有资格接受溶栓或血栓切除术，很大一部分受害者留下明显的功能障碍即使在再灌注治疗之后，再灌注治疗也会增加出血的发生率。在急性中风阶段服用 ArunA 时，通常会导致中风结果恶化。 Bio 的神经干细胞衍生的细胞外囊泡 (NSC EV) 产品可有效缩小病变大小，减轻全身免疫反应，抑制出血性转化，促进功能 NSC EV 可以在再灌注治疗窗口（卒中后 24 小时以上）后施用。单独或辅助 tPA 和/或血栓切除术因此，NSC EV 有改善临床的潜力。 AIS 治疗范例，为粉丝提供现成的、细胞保护和神经恢复的药物生物制剂可促进血管再通后的恢复。该二期项目的总体目标是支持 NSC EV 的研究性新药 (IND) 申请作为AIS的治疗方法，为了推进NSC EV的商业化，顺利完成了 II 期研究将通过在中风中进行明确的药理学和毒理学研究来进行 IND 申请这些目标将通过以下三个具体目标来实现：1）评估 NSC EV 组织分布和大鼠中风模型中的药代动力学，2) 确定大鼠中 NSC EV 剂量反应和相关毒性中风模型，3) 提交 NSC EV 首次人体研究的 IND 申请。在目标 1 中，中风的大鼠将接受高剂量的带有放射性示踪剂标记的 NSC EV 治疗。进行纵向 PET/CT 成像和血液采样以确定 NSC EV 组织分布的动力学在目标 2 中，中风大鼠将接受单剂量或三剂量 NSC EV 方案的治疗。将测量不同浓度、病变大小和感觉运动功能以确定剂量反应。用最高 NSC EV 剂量治疗的大鼠将接受临床和组织病理学分析，以确定任何 NSC EV 相关毒性在目标 3 中，IND 提交的关键组成部分包括这里概述的药理学/毒理学研究以及 CMC 和临床方案将最终确定。 IND申请将提交给FDA，这是首次人体研究和最终研究所必需的商业化。