Amnion cell secretome mediated therapy for traumatic brain injury

羊膜细胞分泌组介导的创伤性脑损伤治疗

• 批准号: 10746655
• 负责人: Benoit Christian Mouzon
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746655
• 关键词: Acute; Address; Adverse event; Affect; Afghanistan; Age; Age Months; Animal Model; Animals; Anxiety; Behavioral; Biochemical; Biochemical Markers; Biological; Biological Markers; Biological Response Modifier Therapy; Blood; Body Weight; Brain Injuries; Brain-Derived Neurotrophic Factor; Cause of Death; Cells; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Data; Deacetylation; Dose; Epigenetic Process; Euthanasia; Exposure to; FDA approved; Family; Female; Goals; Head; Health; Human; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Inflammasome; Inflammation; Inflammatory; Injury; Intervention; Intranasal Administration; Investigational New Drug Application; Investments; Iraq; Knowledge; Learning; Long-Term Effects; Mediating; Medical Research; Memory; Metabolic; Molecular; Motor; Mus; Nervous System Trauma; Outcome; Outcome Measure; Oxidative Stress; Pathologic; Pathology; Patients; Performance; Pharmacotherapy; Phosphorylation; Plasma; Production; Proteins; Proto-Oncogene Proteins c-akt; Quality of life; Recovery; Reporting; Research; Role; SIRT1 gene; Saline; Sensory; Sex Differences; Symptoms; TBI Patients; TBI treatment; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Traumatic Brain Injury; Veterans; Western Blotting; aged; aging population; amnion; brain tissue; clinically relevant; cytokine; effective therapy; functional outcomes; healing; improved; insight; male; manufacture; middle age; mild traumatic brain injury; military veteran; mouse model; neurobehavioral; neurobehavioral test; neuroinflammation; neurological recovery; neuropathology; neuroprotection; novel; novel therapeutic intervention; pre-clinical; preclinical study; prevent; programs; repaired; research clinical testing; sex; standard of care; success; warfighter; white matter

Individuals who have sustained a traumatic brain injury (TBI) have emerged as a significant cause of death to the Warfighters in Iraq and Afghanistan. Whether mild, moderate or severe brain injury, the level of assessment and standard of care provided to the Veteran Population is in need of enhancement. To this end, to expand upon the limited knowledge of the long-term effects of traumatic brain injury, we propose to use our animal model of repetitive-mTBI (r-mTBI) and test a novel treatment to treat/prevent the progression of the chronic pathology following r-mTBI. We hypothesize that a delayed and chronic intranasal treatment with ST266 will mitigate the functional and neuropathological consequences of r-mTBI by improving, cognition, anxiety, sensory and motor function, and with modulation of neuroinflammation in the CNS and in its periphery. ST266 is a proprietary secretome produced by Noveome Biotherapeutics, Inc that contains hundreds of biologically active proteins and other factors that have been shown to be crucial to neuroprotection, modulation of inflammation, cell recovery and healing. The overarching aim of the proposed study is to investigate and refine our understanding of the chronic effects of r-mTBI, using our mouse model of r-mTBI. In addition, this project will investigate the independent association of sex with outcome after r-mTBI with or without treatment with ST266. In the first aim, male and female animals will be exposed to five mTBIs, and then treated daily with a Low or High dose of ST266 delivered intranasally, or saline for a period of 4 months starting at 6 or 18 months post-last injury. The neurobehavioral performance will then be evaluated at both 10- and 22-months post- injury. In the second aim, neuropathological and biochemical analyses will be evaluated at the same time point. Finally, in the third aim, blood biomarkers associated with neurobehavioral recovery such a BDNF or other pro-inflammatory cytokines will be evaluated acutely and chronically post r-mTBI and pre and post ST266 treatment. For each aim, we will evaluate the same outcome measures in female and male mice who have undergone our 5-injury paradigm to identify sex-specific differences. We believe these findings will have broad applicability in TBI research, as the data generated in this study will further the understanding of the complex interaction between ST266 and TBI, and furthermore, we believe this study will provide novel insight into TBI-related pathology and cognitive issues over time in both male and female Veterans. By assessing nuanced aspects of neurobehavioral and pathological deficits, we will provide a framework from which informed decisions can then be made about the cellular and molecular mechanisms that are most important to target to reduce long term TBI-related pathology, and furthermore, which therapeutic intervention strategy best suits the patient. Within 30 months from the start date of this project, we will be able to determine: 1) Which delayed treatment if any, provide neurological recovery based on the behavioral and neuropathological outcome markers; and 2) Preclinical success in the study proposed here will enable Noveome to file an investigational new drug application to conduct a clinical trial specifically addressing this indication which will translate into the improvement of the health or quality of life for Veterans affected by the long-term consequences of r-mTBI.

遭受创伤性脑损伤(TBI)的人已成为重要的死亡原因 伊拉克和阿富汗的战斗人员。无论是轻度、中度还是重度脑损伤， 需要加强对退伍军人的评估和护理标准。对这件事 最后，为了扩大对创伤性脑损伤长期影响的有限知识，我们建议 使用我们的重复mTBI动物模型(r-mTBI)并测试一种新的治疗方法来治疗/防止进展 R-mTBI后的慢性病理改变。 我们假设，延迟和慢性鼻腔治疗ST266将缓解功能性和 R-mTBI改善认知、焦虑、感觉和运动功能的神经病理后果， 中枢神经系统及其外周的神经炎症调节。ST266是一种专有的分泌物 由Noveome BioTreateutics，Inc.生产，含有数百种生物活性蛋白质和其他 已被证明对神经保护、炎症调节、细胞恢复至关重要的因素 以及疗伤。拟议研究的主要目的是调查和完善我们对 R-mTBI的慢性效应，使用我们的r-mTBI小鼠模型。此外，该项目还将调查 使用或不使用ST266治疗的r-mTBI后，性别与预后的独立相关性。 在第一个目标中，雄性和雌性动物将暴露于五种MTBI，然后每天接受低剂量的治疗。 或大剂量ST266鼻腔给药，或从6个月或18个月开始，为期4个月的生理盐水 最后一次受伤后。神经行为表现将在10个月和22个月后进行评估 受伤。在第二个目标中，将同时评估神经病理和生化分析。 指向。最后，在第三个目标中，与神经行为恢复相关的血液生物标记物，如BDNF或 其他促炎细胞因子将在r-mTBI后以及治疗前后进行急性和慢性评估。 ST266治疗。对于每个目标，我们将在雌性和雄性小鼠身上评估相同的结果衡量标准 他们经历了我们的五伤范例，以确定性别差异。我们相信这些发现 将在TBI研究中具有广泛的适用性，因为本研究产生的数据将进一步 了解ST266与脑损伤的复杂相互作用，进一步，我们认为这项研究 将为男性和女性随着时间的推移提供与脑外伤相关的病理和认知问题的新见解 退伍军人。 通过评估神经行为和病理缺陷的细微方面，我们将提供一个框架 从这些信息中可以做出关于细胞和分子机制的明智决定 最重要的目标是减少长期的脑损伤相关病理，而且，哪种治疗方法 干预策略最适合患者。在这个项目开始的30个月内，我们将 能够确定：1)哪种延迟治疗(如果有的话)可根据行为特征提供神经恢复 和神经病理结果标记物；以及2)在这里提出的研究的临床前成功将使 Noveome公司提交了一份研究性新药申请，专门针对这一问题进行临床试验 将转化为改善受影响的退伍军人的健康或生活质量的迹象 R-mTBI的长期后果。