Preclinical Efficacy Failure of Human CNS-Derived Stem Cells for Use in the Pathway Study of Cervical Spinal Cord Injury.
Preclinical Efficacy Failure of Human CNS-Derived Stem Cells for Use in the Pathway Study of Cervical Spinal Cord Injury.
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DOI：
10.1016/j.stemcr.2016.12.018
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发表时间：
2017-02-14
影响因子：
5.9
通讯作者：
Cummings BJ
中科院分区：
文献类型：
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作者：
Anderson AJ;Piltti KM;Hooshmand MJ;Nishi RA;Cummings BJ
我们先前显示了人CNS神经干细胞（HuCNS-SC）的多种研究细胞系（RCL）在胸脊髓损伤（SCI）小鼠和大鼠模型中的疗效，支持胸SCI临床试验。专家建议在模型中对预期的临床细胞批次/细胞系（CCL）进行体内临床前试验，并对计划的临床目标有效。因此，我们测试了两种HuCNS-SC细胞系在颈脊髓损伤中的疗效：一种RCL，一种CCL用于人类颈脊髓损伤的通路研究。我们评估了运动恢复和感觉功能，以及植入、迁移和命运。没有观察到CCL有效性的证据;一些数据表明CCL对结局有负面影响。这些数据提出了关于细胞产品临床检测的效价/可比性试验的开发和验证的问题，以及缺乏美国食品药品监督管理局对预期临床细胞系体内检测的要求。人中枢神经系统干细胞HuCNS-SC的临床细胞系（CCL）在颈脊髓损伤（SCI）模型中无效尽管缺乏体内功效，CCL被用于Pathways临床研究安德森及其同事报道，在颈脊髓损伤（SCI）的人类临床试验中使用，未能在SCI动物模型中显示有效性，而研究级细胞系确实显示有效性。尽管有负面数据，人体试验仍在进行。
We previously showed the efficacy of multiple research cell lines (RCLs) of human CNS neural stem cells (HuCNS-SCs) in mouse and rat models of thoracic spinal cord injury (SCI), supporting a thoracic SCI clinical trial. Experts recommend in vivo preclinical testing of the intended clinical cell lot/line (CCL) in models with validity for the planned clinical target. We therefore tested the efficacy of two HuCNS-SC lines in cervical SCI: one RCL, and one CCL intended for use in the Pathway Study of cervical SCI in man. We assessed locomotor recovery and sensory function, as well as engraftment, migration, and fate. No evidence of efficacy of the CCL was observed; some data suggested a negative impact of the CCL on outcomes. These data raise questions about the development and validation of potency/comparability assays for clinical testing of cell products, and lack of US Food and Drug Administration requirements for in vivo testing of intended clinical cell lines. Human CNS stem cells (HuCNS-SCs) have been used in multiple clinical trials Research cell lines of HuCNS-SCs are efficacious in spinal cord injury (SCI) models The clinical cell line (CCL) of HuCNS-SC was not efficacious in a cervical SCI model Despite lack of in vivo efficacy, the CCL was used in the Pathways clinical study Anderson and colleagues report that preclinical testing of a human neural stem cell line intended for use in a human clinical trial of cervical spinal cord injury (SCI) failed to show efficacy in an animal model of SCI, whereas a research-grade cell line did show efficacy. The human trial proceeded despite the negative data.