Embryonic stem cell therapy after cervical contusion SCI in NHPs

NHP 宫颈挫伤 SCI 后的胚胎干细胞治疗

• 批准号: 9472452
• 负责人: JACQUELINE C BRESNAHAN
• 金额: $ 53.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9472452
• 关键词: Address; Anatomy; Animals; Axon; California; Cell Therapy; Cell Transplants; Cells; Cervical; Cervical spinal cord structure; Chronic; Clinical Research; Contusions; Corticospinal Tracts; Data; Development; Esthesia; Forelimb; Future; Goals; Growth; Hand; Hand functions; Human; Injury; Interneurons; Lesion; Macaca; Magnetic Resonance Imaging; Matched Group; Measures; Modeling; Monkeys; Motor Cortex; Motor Neurons; Muscle; Natural regeneration; Nervous System Trauma; Neurological status; Neurons; Primates; Recovery; Recovery of Function; Reporting; Rodent; Role; Safety; Science; Series; Site; Spastic; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Stem cells; System; Techniques; Technology; Testing; Time; Tracer; Transfection; Translating; Translations; Transplantation; Work; anatomical tracing; base; clinically relevant; cohort; cost; efficacy study; embryonic stem cell; functional outcomes; hand rehabilitation; human embryonic stem cell; improved; myelination; nerve stem cell; nonhuman primate; novel; relating to nervous system; repaired; safety study; spasticity

PROJECT SUMMARY/ABSTRACT This is a new multi-PI proposal from our California Spinal Cord Injury (SCI) consortium to continue to translate exciting results from the transplantation of neural stem cells (NSCs) from rodent to primate, and to evaluate efficacy and safety in our non-human primate (NHP) cervical contusion SCI model. Our multi-center consortium has examined recovery of function and its anatomical correlates in a series of studies using a cervical hemisection model. We have discovered spontaneous and extensive plasticity of the corticospinal tract (CST) system that had not been appreciated in previous rodent studies. We have developed the first large NHP model of cervical hemicontusion SCI together with an open-field scoring system and novel in-cage forelimb activity and hand function tests to evaluate functional outcomes. The wealth of new information and directions speak to the value of this shared approach to using the very valuable primate model. This project focuses on translation of our NHP stem cell work. We now report that neural stem cells (NSCs) derived from human spinal cord grafted early to hemisection sites in NHP SCI, extend very large numbers of axons over very long distances, and that these transplants appear to enhance long-term recovery of hand function, and support CST regeneration into the graft. NSCs derived from the approved human embryonic stem cell H9 (H9 hESCNSCs) also support CST regeneration into spinal cord grafts in the NHP after SCI. Further, we have advanced our cell therapy strategy to produce the first H9 hESCNSCs caudalized to move them towards a spinal cord fate, and have shown that transplants of these cells in rodents promote much more vigorous regeneration of CST axons7. Therefore, in this proposal in NHPs, we will transplant caudalized hESCNSCs into a contusion lesion at a more chronic and clinically relevant six week time point. We hypothesize that these grafts will support robust CST regeneration and enhance recovery of forelimb function, and provide a relay for CST axons to influence forelimb circuitry in the C8-T1 cord. We will use anterograde and retrograde tracing, IHC and transfection of graft cells and correlate the connectional data with recovery, and test the long-term survival, safety, and functional effects of these transplants.

项目摘要/摘要 这是我们加利福尼亚脊髓损伤（SCI）财团的新的多PI提案，继续翻译 神经干细胞（NSC）从啮齿动物到灵长类动物的移植引起的令人兴奋的结果，并评估 我们非人类灵长类动物（NHP）宫颈挫伤模型的功效和安全性。我们的多中心 财团已经检查了功能的恢复及其解剖学相关性在一系列研究中使用 宫颈半分离模型。我们发现了皮质脊髓的自发和广泛的可塑性 （CST）在先前的啮齿动物研究中尚未理解的系统。我们开发了第一个大型NHP 宫颈半污染SCI的模型以及开放场评分系统和新型的笼子内前肢活动 和手功能测试以评估功能结果。大量的新信息和指示与 这种共同方法使用非常有价值的灵长类动物模型的价值。该项目着重于翻译 我们的NHP干细胞工作。 现在，我们报告说，从人脊髓嫁接的人脊髓的神经干细胞（NSC）提早到了半部的部位 NHP SCI，在很长的距离上延伸了大量的轴突，并且这些移植似乎 增强手部功能的长期恢复，并支持CST再生到移植物中。 NSC衍生 批准的人类胚胎干细胞H9（H9 HESCNSCS）也支持CST再生为脊髓 SCI后NHP中的移植物。此外，我们已经提出了细胞疗法策略，以产生第一个H9 HESCNSCS 经过尾声将它们移向脊髓命运，并显示了这些细胞在啮齿动物中的移植 促进CST Axons7的更剧烈的再生。因此，在NHP的此提案中，我们将移植 在更慢性和临床相关的六周时间点中，将hescnscs尾hescnscs缩小为挫伤病变。我们 假设这些移植物将支持强大的CST再生并增强前肢功能的恢复， 并提供CST轴突影响C8-T1线中的前肢电路的继电器。我们将使用顺行 以及逆行跟踪，IHC和移植细胞的转染，并将连接数据与恢复相关联， 并测试这些移植物的长期生存，安全性和功能效应。