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: 8727119
• 负责人: Aileen J Anderson
• 金额: --
• 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/8727119
• 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）：我们先前证明了人类中枢神经系统干细胞（HUCNS-SC）在多种胸部脊髓损伤（SCI）中的临床前功效。 hucns-sc在伤害后9、30和60天移植，生存，迁移，迁移并表现出主要分化为少突胶质细胞和神经元。至关重要的是，移植细胞促进了运动功能的恢复，并且在每个移植时间中没有表现出异源性的迹象。这些数据导致了针对胸腔SCI的长期受伤的个体的I/II期疗程试验；第一名患者于2011年9月在苏黎世大学接受了HUCNS-SC。至关重要的是，有52％的SCI临床病例发生在宫颈水平。靶向慢性SCI人群会产生更大的受试者队列和临床安全性和功效评估的优势（例如，自发恢复是一种显着的混淆）。歧视SCI的治疗诱导的改善部分取决于自发恢复率。急性胸腔受试者自发恢复最高，而在慢性宫颈受试者中最低。据估计，急性胸科SCI试验需要多达225-250个亚洲A受试者和1,100个亚洲B受试者才能检测到中等效应。相反，慢性宫颈SCI试验可能需要25名亚洲A和50名亚洲B受试者。此外，与在胸腔水平上的相似增益相比，宫颈区域的少量功能可以比例更大。我们已经使用免疫缺陷的RAG2G/C小鼠生成了单方面的宫颈SCI模型，以优化异种释放，并证明了HUCNS-SC的9 dPI移植可促进运动效应的恢复，没有不良反应，没有不良反应，建立了HUCNS-SC的前临床效率。 UCI-STEMCELLS Inc.团队已经在使用HUCNS-SC的临床翻译方面拥有丰富的经验，并且已寻求FDA的初步反馈，以供宫颈SCI指示，以预段咨询的形式进行。 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：在60 DPI移植单侧宫颈Sci小鼠模型中，建立HUCNS-SC CCL的功效和测试细胞输送位点。 AIM 3：评估HUCNS-SC CCL在啮齿动物逆转录病毒模型中的安全性。目标4：在既定的单侧宫颈SCI小鼠模型中建立HUCNS-SC CCL的长期安全/毒理学。目标5：如果由FDA在第2年的一次预印本会议上决定，请确定HUCNS-SC的功效和安全/毒理学 使用抗SialogM1抗体治疗的杂种研究设计和宫颈科学大鼠，CCL（ATN大鼠）中的CCL（ATN大鼠）中的CCL。该项目的目的将启用IND应用此HUCNS-SC临床细胞用于宫颈SCI 作为治疗目标。