Exosomes from bone marrow-derived mesenchymal stem cells as a restorative treatment in a non-human primate model of cerebral injury

来自骨髓间充质干细胞的外泌体作为非人灵长类脑损伤模型的恢复治疗

• 批准号: 9371895
• 负责人: TARA L MOORE
• 金额: $ 25.57万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371895
• 关键词: Acute; Address; Animals; Area; Blood Vessels; Bone Marrow; Brain; Brain Injuries; Cell membrane; Cells; Cerebrum; Data; Digit structure; Dose; Electrophysiology (science); Feedback; Female; Future; Hand; Hand functions; Human; Immunohistochemistry; Impairment; Individual; Industry; Infarction; Injectable; Injury; Intravenous infusion procedures; Investigation; Ischemia; Lasers; Lesion; Magnetic Resonance Imaging; Maps; Measures; Mediating; Mesenchymal Stem Cells; Modeling; Monkeys; Morphology; Motor; Motor Cortex; National Institute of Neurological Disorders and Stroke; Nerve Regeneration; Neurologic; Neuronal Plasticity; Neurotransmitter Receptor; Normalcy; Nucleic Acids; Oligodendroglia; Operative Surgical Procedures; Patients; Pattern; Performance; Placebos; Positioning Attribute; Postoperative Period; Proteins; Published Comment; Randomized; Rattus; Recommendation; Recovery; Recovery of Function; Research; Rodent; Role; Scanning; Side; Slice; Stroke; Synapses; Testing; Training; Vesicle; aged; axon growth; base; behavior test; biocytin; density; disability; efficacy testing; exosome; grasp; gray matter; hippocampal pyramidal neuron; improved; in vivo; macromolecule; male; motor function recovery; motor recovery; myelination; neuroprotection; neurorestoration; neurotransmission; nonhuman primate; novel; patch clamp; post stroke; pre-clinical therapy; restorative treatment; stroke therapy; white matter

Abstract/Project Summary In this proposal, we outline our strategy to advance a novel preclinical therapy for the treatment of cortical injury. Our preliminary data in rodents and monkeys indicate that delivery of exosomes derived from bone marrow mesenchymal stem cells (MSCs) aid in functional recovery after cortical injury, likely through enhancement of cortical plasticity. We have gathered in vivo data showing that rats injected with exosomes derived from MSCs score better on behavioral tests for weeks after stroke than animals injected with vehicle control. In keeping with STAIR recommendations that treatments be tested in gyrencephalic animals, such as monkeys, we have begun testing exosomes derived from bone marrow MSCs in our non-human primate model (NHP) of cortical injury. Following injury to primary motor cortex, we administered exosomes and tested recovery in three monkeys. All three monkeys demonstrated functional recovery of fine motor function of the hand that represented a return to pre-injury type of grasp. It is important to note that our preliminary results with only 3 monkeys show an unprecedented level of recovery – monkeys given exosomes showed a pattern and magnitude of fine motor recovery equivalent to a more complete, full recovery of individual digits. This is rarely observed in human patients post-stroke or TBI. These data show the feasibility of this treatment in monkeys and the importance of continued investigation of exosomes as a neuroregenerative treatment. We have previously submitted an expanded version of this proposal twice to NINDS as an R01 application. However, based on reviewer comments requesting that data on the role of exosomes in recovery of function in our model be obtained prior to launching a full-scale study, we now seek support for additional monkeys in order to produce this pilot data. Following the completion of the studies outlined in this proposal, we feel we would then be in a better position to submit a competitive R01 application in the future to conduct an extensive study of exosomes as a novel treatment in our NHP model of cortical injury. Accordingly, we propose two aims. In Aim 1, we will assess the functional recovery after exosome delivery in male and female aged monkeys. In Aim 2, we will measure the effects of exosomes on cortical plasticity by characterizing synaptic and network mechanisms underlying plasticity. This will be the first study to administer exosomes in a NHP model of cortical injury to investigate their role in mediating recovery of function and cortical plasticity. The study is highly translational, and the data gathered in this study will take a step toward developing a safe and translatable neurorestorative therapy.

摘要/项目摘要 在本提案中，我们概述了推进一种新的临床前治疗方法来治疗皮质功能障碍的策略。 受伤。我们在啮齿动物和猴子中的初步数据表明，来自骨的外泌体的递送 骨髓间充质干细胞（MSC）有助于皮质损伤后的功能恢复，可能是通过 增强皮质可塑性。我们收集的体内数据显示，注射外泌体的大鼠 与注射媒介物的动物相比，源自 MSC 的动物在中风后数周的行为测试中得分更高 控制。根据 STAIR 建议，在环脑动物中测试治疗方法，例如 猴子，我们已经开始在我们的非人类灵长类动物模型中测试源自骨髓 MSC 的外泌体 (NHP) 皮质损伤。在初级运动皮层受伤后，我们施用了外泌体并进行了测试 三只猴子康复。所有三只猴子均表现出精细运动功能的功能恢复 代表恢复到受伤前类型的抓握的手。值得注意的是，我们的初步 仅 3 只猴子的结果显示出前所未有的恢复水平——给猴子注射外泌体 显示出精细运动恢复的模式和程度，相当于更完整、全面的恢复 个别数字。这在中风或创伤性脑损伤后的人类患者中很少观察到。这些数据表明 这种治疗方法在猴子中的可行性以及继续研究外泌体作为治疗方法的重要性 神经再生治疗。我们之前已经两次提交了该提案的扩展版本 作为 R01 应用程序提交给 NINDS。然而，根据审稿人的意见，要求提供关于 在开展全面研究之前，应先了解外泌体在我们模型中功能恢复中的作用， 我们现在寻求更多猴子的支持，以产生这一试点数据。继 完成本提案中概述的研究后，我们认为我们将能够更好地 未来提交竞争性的 R01 申请，对外泌体作为外泌体进行广泛的研究 我们的 NHP 皮质损伤模型中的新疗法。因此，我们提出两个目标。在目标 1 中，我们将 评估雄性和雌性老年猴子外泌体递送后的功能恢复。在目标 2 中，我们将 通过表征突触和网络机制来测量外泌体对皮质可塑性的影响 潜在的可塑性。这将是第一项在 NHP 皮质损伤模型中施用外泌体的研究 研究它们在介导功能恢复和皮质可塑性中的作用。该研究具有高度 转化，本研究中收集的数据将朝着开发安全和可靠的方向迈出一步 可转化的神经恢复疗法。