Human Schwann Cell-Derived Exosome Treatment for Traumatic Brain Injury

创伤性脑损伤(TBI)会产生一系列病理生理和行为后果， 严重影响患有这些疾病的人、家庭成员和照顾者的生活质量。这个 成功地将治疗干预措施转化为临床，通过以下方式改善神经学结果 多中心脑损伤试验尚未实现。因此，对小说的持续研究非常有必要。 可能针对多种细胞和分子机制的创伤后治疗策略 脆弱、死亡和修复。我们已经开发了FDA批准的协议来分离和培养数百万 人雪旺细胞(HSC)和最近获得的一种同情用途的研究新药 为了检测HSC衍生的外切体(HSC-Exos)是否存在神经退行性疾病。基于支持性的初步调查 数据，我们建议进行一系列关键研究，以评估最佳剂量和治疗窗口 使用已建立的模型对结构、生化和长期行为结果进行HSC-Exos治疗 严重的脑外伤。我们的总体假设是，脑外伤后静脉注射HSC-Exos将靶向多个 继发性损伤机制以及修复过程导致组织病理学和 长期行为结果。我们建议，这一益处的一个主要机制将包括抗炎 促进细胞保护以及增加内源性修复过程的机会的效果。 我们还建议，根据这项研究的结果，这种方法可以成功地移植到人类身上 因为我们分离HSC-Exos的方法已经得到FDA的批准。特定目标1将评估剂量- HSC-Exos对假手术和脑损伤动物的3个剂量的反应效应。然后，特定目标2将评估 治疗窗内HSC-Exos的最佳剂量对行为和组织病理学结果的影响。在……里面 具体目标3我们将测量包括炎症体在内的炎性介质的时间和区域模式 HSC-Exos治疗后脑组织和血样中的蛋白质。为了具体研究作用机制， 特殊目标4将首次使用最先进的miRNA测序技术评估HSC-Exos货物 信息学方法。在所有研究中，我们将使用穿透性弹道样脑损伤模型在男性和 雌性SD大鼠，临床相关结果测量，生化分析和纳入策略 以增强科学的严谨性和重复性。对于HSC-Exos货物的组装，我们将与 成立公司进行下一代RNA测序和mRNA文库，记录各种 分子作用机制和测试因果关系，同时提供了新的知识 神经创伤领域。这项提案的结果将对神经创伤领域产生重大影响 研究一种新的基于细胞的神经保护疗法，该疗法也可能促进内源性修复过程。 我们提出了一种创新的治疗方法，用于急性和亚急性损伤环境，基于 支持性的初步数据，显然有可能改善这一患者群体的生活质量。

Traumatic brain injury (TBI) produces a spectrum of pathophysiological and behavioral consequences that severely affect the quality of life of people living with these disorders, family members and caregivers. The successful translation of therapeutic interventions to the clinic to improve neurological outcomes through multicenter TBI trials is yet to be achieved. There is therefore a great need for continued research into novel post-traumatic therapeutic strategies that may target multiple cellular and molecular mechanisms of cell vulnerability, death and repair. We have developed FDA-approved protocols to isolate and grow millions of human Schwann cells (hSC) and have most recently received a compassionate use Investigational New Drug to test hSC-derived exosomes (hSC-Exos) for a neurodegenerative disorder. Based on supportive preliminary data, we propose to conduct a series of critical studies to evaluate the optimal dose and therapeutic window for hSC-Exos treatment on structural, biochemical, and long-term behavioral outcomes using an established model of severe TBI. Our overall hypothesis is that intravenous administration of hSC-Exos after TBI will target multiple secondary injury mechanisms as well as reparative processes leading to improved histopathological and longterm behavioral outcomes. We propose that a major mechanism for this benefit will include anti-inflammatory effects that will promote cytoprotection as well as enhance the opportunity for endogenous reparative processes. We also suggest that this approach can be successfully translated into humans based on the results of this study as our approach of isolating the hSC-Exos has been approved by the FDA. Specific Aim 1 will evaluate the dose- response effects (3 doses) of the hSC-Exos in sham operated and TBI animals. Specific Aim 2 will then evaluate the optimal dose of hSC-Exos on the therapeutic window on behavioral and histopathological outcomes. In Specific Aim 3 we will measure temporal and regional pattens of inflammatory mediators including inflammasome proteins in brain and blood samples after hSC-Exos treatment. To specifically study mechanisms of action, Specific Aim 4 will evaluate the hSC-Exos cargo for the first time using state-of-the-art miRNA sequenceing and informatic approaches. For all studies, we will utilize the penetrating ballistic-like brain injury model in male and female Sprague Dawley rats, clinically relevant outcome measures, biochemical analyses and include strateges to enhance scientific rigor and reproducibility. For the assemment of the hSC-Exos cargo, we will work with an established company to conduct next generation RNA sequencing and mRNA libraries, document the various molecular mechanisms of action and test cause and effect relationships while providing new knowledge to this field of neurotrauma. The results of this proposal will have a significant impact on the field of neurotrauma by investigating a new cell based neuroprotective therapy that may also promote endogenous reparative processes. We propose an innovative therapeutic approach to be used in the acute and subacute injury settings based on supportive preliminary data which clearly has the potential to improve the quality of life in this patient population.