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）的个体已成为死亡的重要原因 给伊拉克和阿富汗的战士。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。本 最后，为了扩大对创伤性脑损伤长期影响的有限认识，我们建议 使用我们的重复性mTBI（r-mTBI）动物模型，并测试一种新的治疗方法来治疗/预防进展 r-mTBI后的慢性病理学。 我们假设用ST 266进行延迟和慢性鼻内治疗将减轻功能性和 通过改善认知、焦虑、感觉和运动功能， 以及调节CNS及其周围的神经炎症。ST 266是一种专有的分泌蛋白质组 由Noveome Biotherapeutics，Inc生产，含有数百种生物活性蛋白质和其他 这些因子已被证明对神经保护、炎症调节、细胞恢复 和治愈。拟议研究的总体目标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 性别与r-mTBI后用或不用ST 266治疗的结果的独立关联。 在第一个目标中，雄性和雌性动物将暴露于5个mTBI，然后每天用低剂量的 或鼻内递送高剂量ST 266，或生理盐水，从6或18个月开始，持续4个月 最后一次受伤然后在术后10个月和22个月评估神经行为表现， 损伤在第二个目标中，将同时评估神经病理学和生化分析 点最后，在第三个目标中，与神经行为恢复相关的血液生物标志物，例如脑源性神经营养因子或 其他促炎细胞因子将在r-mTBI后急性和慢性评价， ST 266治疗。对于每一个目标，我们将在雌性和雄性小鼠中评估相同的结果指标 他们经历了我们的5次伤害模式，以确定性别特异性差异。我们相信这些发现 将在TBI研究中具有广泛的适用性，因为本研究中产生的数据将进一步 了解ST 266和TBI之间的复杂相互作用，此外，我们相信这项研究 将为男性和女性TBI相关的病理学和认知问题提供新的见解 老兵 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， 从中可以做出关于细胞和分子机制的明智决定， 最重要的是以减少长期TBI相关病理为目标，此外， 干预策略最适合患者。在本项目开始之日起30个月内，我们将 能够确定：1）哪种延迟治疗（如果有）根据行为提供神经恢复 和神经病理学结果标志物;和2）本文提出的研究的临床前成功将使 Noveome提交研究性新药申请，以进行专门针对此问题的临床试验 表明这将转化为改善健康或生活质量的退伍军人影响， r-mTBI的长期后果。