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

摘要/项目摘要 在这项提案中，我们概述了我们的战略，以推进一种新的临床前治疗皮质炎的方法。 受伤。我们在啮齿动物和猴子身上的初步数据表明，来自骨骼的外切体的交付 骨髓间充质干细胞有助于皮质损伤后的功能恢复，可能通过 增强皮质的可塑性。我们收集的活体数据显示，注射外切体的大鼠 在中风后数周的行为测试中，来源于MSCs的动物比注射了车辆的动物得分更高 控制力。为了与STRISE的建议保持一致，治疗应该在轮脑动物身上进行测试，例如 猴子们，我们已经开始在我们的非人类灵长类动物模型中测试来自骨髓间充质干细胞的外体 皮质损伤(NHP)。在初级运动皮质损伤后，我们使用外切体并测试 三只猴子的康复。所有三只猴子均表现出精细运动功能的恢复。 这只手代表着回到受伤前的握力类型。值得注意的是，我们的初步计划 只有3只猴子的结果显示出前所未有的恢复水平--给猴子注射外切体 显示了精细运动恢复的模式和幅度，相当于更完全、完全的恢复 个位数。这在人类中风或脑外伤后的患者中很少观察到。这些数据表明， 这种疗法在猴子身上的可行性以及继续研究外切体作为一种治疗方法的重要性 神经再生治疗。我们之前已经两次提交了这项提案的扩展版本 作为R01应用程序添加到NINDS。然而，根据评论家的评论，要求在 在我们的模型中，在启动一项全面的研究之前，需要获得外切体在功能恢复中的作用， 我们现在寻求对更多猴子的支持，以产生这个试验数据。紧随其后的是 完成这项建议中概述的研究后，我们认为我们将更好地 在未来提交竞争性的R01申请，以进行广泛的Exosome研究 我们的NHP皮质损伤模型中的新治疗方法。因此，我们提出了两个目标。在目标1中，我们将 评价雌雄老龄猴外胚体分娩后的功能恢复情况。在目标2中，我们将 通过表征突触和网络机制来测量外体对皮质可塑性的影响 潜在的可塑性。这将是第一个在NHP皮质损伤模型中应用外切体的研究 研究它们在调节功能恢复和皮质可塑性中的作用。这项研究是高度 翻译，在这项研究中收集的数据将朝着开发安全和 可翻译的神经恢复性疗法。

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.