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.

项目总结/文摘