Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study
Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study
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重复蛛网膜下腔注射同种异体人脐带间充质干细胞治疗脊髓损伤：1/2 期试点研究
DOI：
10.1016/j.jcyt.2020.09.012
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发表时间：
2021-01-01
期刊：
影响因子：
4.5
通讯作者：
Rong, Li-Min
中科院分区：
文献类型：
--
作者：
Yang, Yang;Pang, Mao;Rong, Li-Min
背景目标：干细胞移植是治疗难治性脊髓损伤（SCI）的一种潜在方法，hUC-MSCs具有免疫赦免、旁分泌、免疫调节、采集方便、伦理问题少等优点，是一种很有前途的细胞来源，目前迫切需要开发一种安全有效的临床应用方案。进行了一项前瞻性、单中心、单臂研究，其中受试者每月接受4次hUC-MSCs蛛网膜下腔移植（1 106个细胞/kg），并在随访中观察4次（末次给药后1、3、6和12个月）。在每个计划时间点，收集安全性和有效性指标并进行相应分析。不良事件（AE）用作安全性指标。美国脊髓损伤协会（ASIA）和国际神经病学协会SCI功能评定量表将第4次随访时的IANR-SCIFRS总评分确定为主要疗效结局，而其余时间点的这两项指标以及针刺、轻触、运动和括约肌、肌肉痉挛和痉挛、自主神经系统、膀胱和肠功能评分，残余尿量（RUV）和磁共振成像（MRI）是次要疗效结局。结果：分别对102例和41例受试者进行了安全性和有效性评估。在hUC-MSC移植后观察到轻度AE，包括发热（14.1%）、头痛（4.2%）、肌张力一过性增加（1.6%）和头晕（1.3%），并在保守治疗后彻底消退。未发生严重AE。研究期间不同时间点的ASIA和IANR-SCIFRS总评分与基线相比均有统计学增加，主要体现在针刺、轻触、运动和括约肌评分的改善。此外，受试者的肌肉痉挛持续显著减少。关于肌肉痉挛、自主神经系统、膀胱和肠功能、RUV和MRI，最终随访时的数据/成像显示与首次采集时相比有显著改善。亚组分析发现，hUC-MSC移植改善了神经功能，而不管损伤特征，包括水平、严重程度和慢性程度。结论：作者的本方案表明，鞘内施用同种异体hUCMSC，剂量为10（6）个细胞/kg，每月一次，持续4个月，是安全有效的，并导致神经功能障碍的显著改善和生活质量的恢复。(C)2020国际细胞与基因治疗学会爱思唯尔公司出版All rights reserved.
Background aims: Stem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application.Methods: A prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed.Results: Safety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity.Conclusions: The authors' present protocol demonstrates that intrathecal administration of' allogeneic hUCMSCs at a dose of 10(6) cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life. (C) 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.