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

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）在多种啮齿动物胸椎脊髓损伤（SCI）模型中的临床前疗效。huns - sc在损伤后9、30和60天（dpi）移植，移植、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，并且在每次移植时都没有显示异常性疼痛的证据。这些数据促成了一项针对胸部SCIs慢性损伤患者的I/II期SwissMedic试验；第一位患者于2011年9月在苏黎世大学接受了huns - sc。关键的是，52%的SCIs临床病例发生在颈椎水平。针对慢性脊髓损伤人群，可以产生更大的受试者队列，并且在临床安全性和有效性评估方面具有优势（例如，急性自发性恢复是一个显著的混淆）。在一定程度上，对脊髓损伤治疗改善的区别取决于患者的自发恢复率。自发性恢复在急性胸椎患者中最高，在慢性颈椎患者中最低。一项急性胸椎脊髓损伤试验估计需要225-250名ASIA A受试者和1100名ASIA B受试者才能检测到中度效果。相比之下，慢性颈椎损伤试验可能只需要25名ASIA a受试者和50名ASIA B受试者。此外，与胸椎水平相似的功能增强相比，颈椎区域功能的小幅增强在生活质量上的比例变化更大。我们利用免疫缺陷的Rag2g/c小鼠建立了单侧颈椎脊髓损伤模型，优化异种移植，并证明9 dpi移植HuCNS-SC促进运动功能恢复，无不良反应，建立了HuCNS-SC的临床前疗效。UCI-StemCells公司的团队已经在使用huns - sc的临床转化方面拥有相当丰富的经验，并且已经以pre-preIND咨询的形式向FDA寻求宫颈SCI适应症的初步反馈。该提案基于我们与FDA的互动，旨在扩大我们目前的颈椎脊髓损伤疗效数据，以评估HuCNS-SC的预期临床细胞批的疗效和长期安全性/毒理学，解决以下具体目标：目标1：在9 dpi移植单侧颈椎脊髓损伤小鼠模型中建立HuCNS-SC CCL的疗效和测试细胞递送位点。目的2：建立huns - sc CCL在60 dpi移植单侧颈椎脊髓损伤小鼠模型中的疗效并测试细胞递送部位。目的3：评估huns - sc CCL在自主神经反射障碍啮齿动物模型中的安全性。目的4：建立huns - sc CCL在已建立的单侧颈椎损伤小鼠模型中的长期安全性/毒理学。目标5：如果FDA在第2年的ind前会议上要求，建立huns - sc的有效性和安全性/毒理学

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.