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

• 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
• 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

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）产生一系列病理生理和行为后果， 严重影响这些疾病患者、家庭成员和照顾者的生活质量。的 成功地将治疗干预转化为临床，通过以下方式改善神经系统结局： 多中心TBI试验尚未完成。因此，对小说的研究仍有很大的必要 创伤后治疗策略，可以针对多种细胞和分子机制的细胞 脆弱，死亡和修复我们已经开发出FDA批准的方案， 人雪旺细胞（hSC），最近接受了体恤使用的研究性新药 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的关键研究，以评估最佳剂量和治疗窗口， 使用已建立的模型对hSC-Exos治疗对结构、生化和长期行为结果的影响 严重的TBI。我们的总体假设是，TBI后静脉内施用hSC-Exos将靶向多个靶点。 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。我们认为，一个主要的机制，这一好处将包括抗炎 这将促进细胞保护以及增强内源性修复过程的机会的作用。 我们还建议，根据这项研究的结果，这种方法可以成功地转化为人类 因为我们分离hSC-Exos的方法已经被FDA批准。具体目标1将评估剂量- hSC-Exos在假手术和TBI动物中的反应效果（3个剂量）。具体目标2将评估 hSC-Exos在治疗窗口对行为和组织病理学结果的最佳剂量。在 具体目标3我们将测量包括炎性小体在内的炎性介质的时间和区域模式 在hSC-Exos处理后脑和血液样品中的蛋白质。专门研究作用机制， Specific Aim 4将首次使用最先进的miRNA测序技术评估hSC-Exos货物， 信息方法。对于所有的研究，我们将利用穿透性弹道样脑损伤模型， 雌性Sprague道利大鼠，临床相关结果测量，生化分析和包括策略 以提高科学的严谨性和可重复性。为了组装hSC-Exos货物，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，同时提供新的知识， 神经创伤领域。该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，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的基础上， 支持性初步数据，明显具有改善该患者人群生活质量的潜力。