Human neural stem cell therapy for the treatment of cervical spinal cord injury (

人类神经干细胞疗法治疗颈脊髓损伤（

• 批准号: 8503499
• 负责人: Aileen J Anderson
• 金额: $ 226.44万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503499
• 关键词: Acute; Address; Adverse effects; American; Animals; Antibodies; Autonomic Dysreflexia; Axon; Behavioral; Bilateral; Biological Assay; Brain; Cations; Cell Transplants; Cells; Cervical; Cervical spinal cord injury; Chest; Chronic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Data Monitoring Committees; Cognitive; Collaborations; Consultations; Contusions; Data; Data Analyses; Development; Discrimination; Engraftment; Enrollment; Esthesia; Exhibits; Feedback; Human; Hybrids; Hyperalgesia; Immunodeficient Mouse; Immunosuppression; Individual; Injury; Light; Locomotor Recovery; Modeling; Motor; Mus; Neuraxis; Neuronal Ceroid-Lipofuscinosis; Neurons; Neurosurgeon; Oligodendroglia; Outcome Measure; Patients; Pelizaeus-Merzbacher Disease; Performance; Phase; Phase I Clinical Trials; Phenotype; Population; Pregnancy; Principal Investigator; Quality of life; Rattus; Recovery; Recovery of Function; Regulatory Affairs; Reporting; Research Design; Rodent Model; Safety; Scientist; Sensory; Site; Spinal cord injury; Spinal cord injury patients; Stem cell transplant; Stem cells; Testing; Therapeutic; Thoracic spinal cord structure; Time; Touch sensation; Toxicology; Translations; Transplantation; Universities; Xeno; Xenograft procedure; allodynia; base; clinical efficacy; cohort; efficacy testing; experience; fetal; gain of function; in vivo; injured; meetings; migration; mouse model; myelination; nerve stem cell; nervous system transplantation; nonhuman primate; pre-clinical; programs; safety study; stem cell therapy; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): We previously demonstrated pre-clinical efficacy of Human Central Nervous System Stem Cells (HuCNS-SC) in multiple rodent models of thoracic spinal cord injury (SCI). HuCNS-SC transplanted at 9, 30, and 60 days post-injury (dpi) engraft, survive, migrate, and exhibit predominant differentiation into oligodendrocytes and neurons. Critically, transplanted cells promoted recovery of locomotor function and showed no evidence of allodynia at each of these transplantation times. These data contributed to a Phase I/II SwissMedic trial targeting chronically injured individuals suffering from thoracic SCIs; the first patient received HuCNS-SC in September 2011 at the University of Zurich. Critically, 52% of clinical cases of SCIs occur at the cervical level. Targeting the chronic SCI population yields a much larger subject cohort and advantages for clinical safety and efficacy assessment (e.g. spontaneous recovery is a significant confound acutely). Discrimination of a therapy induced improvement for SCI is dependent, in part, on the spontaneous recovery rate. Spontaneous recovery is highest in acute thoracic subjects, and lowest in chronic cervical subjects. An acute thoracic SCI trial has been estimated to require as many as 225-250 ASIA A subjects and 1,100 ASIA B subjects to detect a moderate effect. In contrast, a chronic cervical SCI trial may require as few as 25 ASIA A subjects, and 50 ASIA B subjects. Further, a small gain of function in the cervical region affords a proportionally greater change in quality of life compared to a similar gain at the thoracic level. We have generated a unilateral cervical SCI model using immunodeficient Rag2g/c mice to optimize xeno-engraftment, and demonstrated that 9 dpi transplantation of HuCNS-SC promotes recovery of locomotor function with no adverse effects, establishing pre-clinical efficacy of HuCNS-SC. The UCI-StemCells Inc. team already has considerable experience in clinical translation using HuCNS-SC and has sought preliminary feedback from the FDA for a cervical SCI indication in the form of a pre-preIND consultation. This proposal is based on our FDA interactions and seeks to expand our current cervical SCI efficacy data to evaluate the intended clinical cell lot of HuCNS-SC for both efficacy and long-term safety/toxicology addressing the following Specific Aims: Aim 1: Establish efficacy and test cell delivery site for the HuCNS-SC CCL in a 9 dpi transplantation unilateral cervical SCI mouse model. Aim 2: Establish efficacy and test cell delivery site for the HuCNS-SC CCL in a 60 dpi transplantation unilateral cervical SCI mouse model. Aim 3: Assess the safety of the HuCNS-SC CCL in a rodent model of autonomic dysreflexia. Aim 4: Establish long-term safety/toxicology of the HuCNS-SC CCL in the established unilateral cervical SCI mouse model. Aim 5: If dictated by the FDA in a pre-IND meeting in Year 2, establish efficacy and safety/toxicology for the HuCNS-SC CCL in a second species (ATN rat), using a hybrid study design and cervical SCI rats receiving supplemental immunosuppression with anti-sialoGM1 antibody treatment. The aims of this project will enable IND application for the use of this HuCNS-SC clinical cell lot for cervical SCI as a therapeutic target.

描述（由申请人提供）：我们之前证明了人类中枢神经系统干细胞（HuCNS-SC）在胸脊髓损伤（SCI）的多种啮齿动物模型中的临床前功效。在损伤后 9、30 和 60 天 (dpi) 移植的 HuCNS-SC 植入、存活、迁移并表现出向少突胶质细胞和神经元的主要分化。重要的是，移植的细胞促进了运动功能的恢复，并且在每个移植时间都没有显示出异常性疼痛的证据。这些数据促成了 SwissMedic 针对患有胸部 SCI 的慢性损伤患者的 I/II 期试验；首例患者于 2011 年 9 月在苏黎世大学接受了 HuCNS-SC 治疗。至关重要的是，52% 的 SCI 临床病例发生在颈部。以慢性 SCI 人群为目标，可以产生更大的受试者群体，并有利于临床安全性和疗效评估（例如，自发恢复是一个严重的混杂因素）。对治疗引起的 SCI 改善的区分部分取决于自发恢复率。急性胸部受试者的自发恢复最高，而慢性颈椎受试者的自发恢复最低。据估计，一项急性胸部 SCI 试验需要多达 225-250 名 ASIA A 受试者和 1,100 名 ASIA B 受试者才能检测到中等效果。相比之下，慢性颈椎 SCI 试验可能只需要 25 名 ASIA A 受试者和 50 名 ASIA B 受试者。此外，与胸部水平的类似功能增益相比，颈部区域的小幅功能增益可带来更大的生活质量变化。我们使用免疫缺陷的 Rag2g/c 小鼠建立了单侧颈椎 SCI 模型来优化异种移植，并证明 HuCNS-SC 的 9 dpi 移植可促进运动功能的恢复，且无不良影响，从而确立了 HuCNS-SC 的临床前疗效。 UCI-StemCells Inc. 团队在使用 HuCNS-SC 进行临床转化方面已经拥有丰富的经验，并以 pre-preIND 咨询的形式寻求 FDA 对宫颈 SCI 适应症的初步反馈。该提案基于我们与 FDA 的互动，旨在扩展我们当前的颈椎 SCI 疗效数据，以评估 HuCNS-SC 的预期临床细胞批次的功效和长期安全性/毒理学，解决以下具体目标： 目标 1：在 9 dpi 移植单侧颈椎 SCI 小鼠模型中建立 HuCNS-SC CCL 的功效和测试细胞递送位点。目标 2：在 60 dpi 移植单侧颈椎 SCI 小鼠模型中建立 HuCNS-SC CCL 的功效并测试细胞递送位点。目标 3：评估 HuCNS-SC CCL 在自主神经反射障碍啮齿动物模型中的安全性。目标 4：在已建立的单侧颈椎 SCI 小鼠模型中建立 HuCNS-SC CCL 的长期安全性/毒理学。目标 5：如果 FDA 在第 2 年的 IND 前会议上提出要求，则确定 HuCNS-SC 的功效和安全性/毒理学 第二种物种（ATN 大鼠）的 CCL，采用混合研究设计，颈椎 SCI 大鼠接受抗 sialoGM1 抗体治疗的补充免疫抑制。该项目的目标是使 HuCNS-SC 临床细胞批用于颈椎 SCI 的 IND 申请成为可能 作为治疗靶点。