Embryonic Stem Cell Therapy after Cervical Contusion SCI in NHPs

这一新的应用代表了加州灵长类脊髓研究的延续 人胚胎干细胞(HESC)来源神经干细胞联合项目 移植；我们的首要目标是了解脊髓的两种基本机制 非人灵长类的组织和功能，并利用这些和其他方面的进展 开发转化型人类促再生疗法。我们已经取得了相当大的进展 在过去5年中取得的进展，现在提出新的具体目标，这些目标将直接与 人类神经干细胞(NSCs)造福人类脊髓损伤的潜力。 目标1：检查移植物相关功能改善的机制：移植物 用抑制性DREADD沉默。为实现这一目标所做的工作将确定 在非人类灵长类动物中观察到的脊髓化神经干细胞移植后的恢复与 移植物激活宿主神经回路。这些知识对人类翻译将是重要的。 目的2：确定4-AP是否改善术后的解剖和功能结果 神经干细胞移植有大量的文献支持潜在的有益作用 4AP在脊髓损伤中的作用，4AP被批准作为一种多用途的传导增强药物用于人类 硬化症。这一目标将决定神经干细胞移植加4AP治疗是否 改善解剖和功能结果。 目的3：确定抑制PTEN/SOCS3是否改善宿主皮质脊髓 再生和功能结果。啮齿动物研究表明， 神经干细胞移植是由宿主-移植物-宿主电生理的形成所介导的 跨SCI地点的转播。这些中继器需要宿主轴突再生为移植物。在人类身上， 皮质脊髓轴突对于自主运动是必不可少的。这一目标将决定是否 PTEN/SOCS3失活将促进皮质脊髓轴突再生并改善 灵长类动物的功能结果。

This new application represents a continuation of the California Primate Spinal Cord Research Consortium project on human embryonic stem cell (hESC) derived neural stem cell transplantation; our overarching goal is to understand both basic mechanisms of spinal cord organization and function in non-human primates, and to leverage these and other advances in developing translational human pro-regenerative therapies. We have made considerable progress in the last 5 years and now propose new specific aims that will directly bear on the potential of human neural stem cells (NSCs) to benefit human SCI. Aim 1: Examine Mechanisms Underlying Graft-Related Functional Improvement: Graft Silencing with Inhibitory DREADDs. Work in this aim will establish whether functional recovery observed in non-human primates after grafts of spinalized neural stem cells is related to graft activation of host neural circuits. This knowledge will be important for human translation. Aim 2: Determine Whether 4-AP Improves Anatomical and Functional Outcomes After Neural Stem Cell Grafts There is a vast literature supporting potentially beneficial effects of 4AP in SCI, and 4AP is approved for human use as a conduction-enhancing drug in multiple sclerosis. This aim will determine whether treatment with neural stem cell grafts plus 4AP improves anatomical and functional outcomes. Aim 3: Determine Whether PTEN/SOCS3 Inhibition Improves Host Corticospinal Regeneration and Functional Outcomes. Rodent studies indicate that functional benefits of neural stem cell grafts are mediated by formation of host-to-graft-to-host electrophysiological relays across sites of SCI. These relays require host axon regeneration into grafts. In humans, corticospinal axons are essential for voluntary movement. This aim will determine whether inactivation of PTEN/SOCS3 will enhance corticospinal axon regeneration and improve functional outcomes in primates.