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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

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）产生一系列的病理生理和行为后果