Human Schwann Cell-Derived Exosome Treatment for Traumatic Brain Injury

人雪旺细胞衍生的外泌体治疗创伤性脑损伤

基本信息

批准号：
10714644
负责人：
W Dalton Dietrich
金额：
$ 40.75万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714644
关键词：
Acute Affect Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Ballistics Behavioral Biochemical Biological Process Blood specimen Brain Brain Injuries Brain region CASP1 gene Caregivers Cause of Death Cell Culture Techniques Cell Death Cell Therapy Cell Transplantation Cells Cessation of life Chronic Clinic Clinical Trials Complex Cytoprotection Data Disease Dose Early treatment Effectiveness Emergency department visit FDA approved Family member Female Functional disorder Future Good Manufacturing Process Heart Arrest Histologic Hospitalization Human Human Characteristics IL18 gene Immune Inflammasome Inflammation Inflammation Mediators Inflammatory Informatics Injury Innate Immune System Interleukin-1 beta Investigational Drugs Ischemic Stroke Knowledge Libraries Measures Mediator Messenger RNA MicroRNAs Modality Modeling Molecular Molecular Mechanisms of Action Morbidity - disease rate Multiprotein Complexes Nervous System Trauma Neurodegenerative Disorders Neurological outcome Neurons Outcome Outcome Measure Pathologic Pattern Penetration Peripheral nerve injury Persons Physiological Play Population Property Proteins Protocols documentation Quality of life Reporting Reproducibility Research Role Safety Sampling Schwann Cells Series Serum Signal Transduction Spinal Cord Sprague-Dawley Rats TBI treatment Testing Therapeutic Therapeutic Intervention Time Translating Translations Traumatic Brain Injury Treatment Protocols United States Work amyotrophic lateral sclerosis therapy axon regeneration behavioral outcome bone repair cell type clinical translation clinically relevant disability exosome first-in-human functional improvement improved improved outcome innovation intravenous administration male miRNA expression profiling mortality myelination neurite growth neuroprotection next generation next generation sequencing novel patient population pre-clinical programs protein expression regenerative repaired reparative process response spinal cord and brain injury success targeted treatment therapeutic target time use transcriptome sequencing translational potential translational therapeutics treatment strategy

Acute Affect Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Ballistics Behavioral Biochemical Biological Process Blood specimen Brain Brain Injuries Brain region CASP1 gene Caregivers Cause of Death Cell Culture Techniques Cell Death Cell Therapy Cell Transplantation Cells Cessation of life Chronic Clinic Clinical Trials Complex Cytoprotection Data Disease Dose Early treatment Effectiveness Emergency department visit FDA approved Family member Female Functional disorder Future Good Manufacturing Process Heart Arrest Histologic Hospitalization Human Human Characteristics IL18 gene Immune Inflammasome Inflammation Inflammation Mediators Inflammatory Informatics Injury Innate Immune System Interleukin-1 beta Investigational Drugs Ischemic Stroke Knowledge Libraries Measures Mediator Messenger RNA MicroRNAs Modality Modeling Molecular Molecular Mechanisms of Action Morbidity - disease rate Multiprotein Complexes Nervous System Trauma Neurodegenerative Disorders Neurological outcome Neurons Outcome Outcome Measure Pathologic Pattern Penetration Peripheral nerve injury Persons Physiological Play Population Property Proteins Protocols documentation Quality of life Reporting Reproducibility Research Role Safety Sampling Schwann Cells Series Serum Signal Transduction Spinal Cord Sprague-Dawley Rats TBI treatment Testing Therapeutic Therapeutic Intervention Time Translating Translations Traumatic Brain Injury Treatment Protocols United States Work amyotrophic lateral sclerosis therapy axon regeneration behavioral outcome bone repair cell type clinical translation clinically relevant disability exosome first-in-human functional improvement improved improved outcome innovation intravenous administration male miRNA expression profiling mortality myelination neurite growth neuroprotection next generation next generation sequencing novel patient population pre-clinical programs protein expression regenerative repaired reparative process response spinal cord and brain injury success targeted treatment therapeutic target time use transcriptome sequencing translational potential translational therapeutics treatment strategy

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项目摘要

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.

创伤性脑损伤（TBI）会产生各种各样的病理生理和行为后果严重影响患有这些疾病，家庭成员和看护人的人们的生活质量。这成功地将治疗干预措施转化为诊所，以改善神经系统结局多中心TBI试验尚未实现。因此，需要继续研究小说可能针对细胞多种细胞和分子机制的创伤后治疗策略脆弱性，死亡和修复。我们已经开发了FDA批准的协议，以隔离和增加数百万人类Schwann细胞（HSC），最近收到了富有同情心的使用调查新药测试HSC衍生的外泌体（HSC-exos）的神经退行性疾病。基于支持性初步数据，我们建议进行一系列批判性研究，以评估最佳剂量和治疗窗口 HSC-Exos对结构，生化和长期行为结果的治疗使用已建立的模型严重的TBI。我们的总体假设是，TBI之后的HSC-EXO静脉内给药将针对多个次要伤害机制以及修复过程，导致组织病理学改善和长期行为结果。我们建议，该收益的主要机制将包括抗炎将促进细胞保护并增强内源性修复过程的机会。我们还建议，可以根据这项研究的结果成功地将这种方法成功地转化为人类由于我们隔离HSC-Exos的方法已获得FDA的批准。特定目标1将评估剂量 - 在假手术和TBI动物中，HSC-exos的反应效应（3剂）。特定目标2然后评估在行为病理学结果上的治疗窗口上HSC-exos的最佳剂量。在特定目的3我们将测量包括炎症体的炎症介质的时间和区域性刺激 HSC-EXOS治疗后脑和血液样本中的蛋白质。专门研究作用机制，特定AIM 4将使用最先进的miRNA序列和信息方法。对于所有研究，我们将在男性和女性Sprague Dawley大鼠，临床相关的结果指标，生化分析并包括策略增强科学严谨性和可重复性。对于HSC-Exos货物的大会，我们将与成立的公司进行下一代RNA测序和mRNA库，记录各种在为此提供新知识的同时，行动和测试因果关系的分子机制 Neurotrauma领域。该提案的结果将对神经瘤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，该治疗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，用于基于急性和亚急性伤害设置支持性初步数据显然有可能改善该患者人群的生活质量。