脐血单核细胞移植治疗慢性完全性脊髓损伤Ⅱ期临床试验的安全性和疗效评估

doi:10.3877/cma.j.issn.2095-9141.2020.04.002

中华神经创伤外科电子杂志 ›› 2020, Vol. 06 ›› Issue (04) : 196 -201. doi: 10.3877/cma.j.issn.2095-9141.2020.04.002

所属专题：专题评论；文献；

临床研究

脐血单核细胞移植治疗慢性完全性脊髓损伤Ⅱ期临床试验的安全性和疗效评估

封亚平¹^,^†(

), Wise Young², 朱辉¹, 封雨¹, 邓洵鼎¹, 谢佳芯¹, 张社敏¹, 方芳¹, 石静¹, 陈永和³, 郑爽³

^1. 650032　昆明，联勤保障部队第九二〇医院神经外科
^2. 08855　美国皮斯卡特维，美国新泽西罗格斯州立大学神经科学中心
^3. 999077　香港，中国脊髓损伤研究协作组

收稿日期:2020-01-28 出版日期:2020-08-15
通信作者: 封亚平
基金资助:
军队临床高新技术重大项目(2010gxjs042); 云南省社会发展科技计划项目(2010CA005)

Phase Ⅱ clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury

Yaping Feng¹^,^†(), Wise Young², Hui Zhu¹, Yu Feng¹, Xunding Deng¹, Jiaxin Xie¹, Shemin Zhang¹, Fang Fang¹, Jing Shi¹, Yonghe Chen³, Shuang Zheng³

^1. Department of Neurosurgery, 920 Hospital of Joint Logistics Support Force, Kunming 650032, China
^2. W.M. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway 08855, New Jersey, United States
^3. China Spinal Cord Injury Network, Hong Kong 999077, China

Received:2020-01-28 Published:2020-08-15
Corresponding author: Yaping Feng
About author:
Corresponding author: Feng Yaping, Email: fengyp888@aliyun.com

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封亚平, Wise Young, 朱辉, 封雨, 邓洵鼎, 谢佳芯, 张社敏, 方芳, 石静, 陈永和, 郑爽. 脐血单核细胞移植治疗慢性完全性脊髓损伤Ⅱ期临床试验的安全性和疗效评估[J]. 中华神经创伤外科电子杂志, 2020, 06(04): 196-201.

Yaping Feng, Wise Young, Hui Zhu, Yu Feng, Xunding Deng, Jiaxin Xie, Shemin Zhang, Fang Fang, Jing Shi, Yonghe Chen, Shuang Zheng. Phase Ⅱ clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury[J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2020, 06(04): 196-201.

目的

评估人类白细胞抗原（HLA≥4:6）配型的脐血单核细胞（UCBMC）移植治疗慢性完全性脊髓损伤（SCI）的安全性、可行性、有效性以及最佳细胞剂量和联合使用甲基强的松龙（MP）、碳酸锂对细胞移植的作用。

方法

选取联勤保障部队第九二〇医院神经外科自2011年2月至2014年1月收治的20例SCI患者，按照随机数字表法分为5组（A、B、C、D、E组），每组4例受试者。在患者损伤上下缘脊神经背根入处的4个点（上下各2点）注射UCBMC，A、B、C组分别为每点各注射4、8和16 μL（100 000 UCBMC/μL，640万细胞）到SCI部位的上方和下方脊神经背根入处，D组为16 μL细胞注射加30 mg/kg MP静脉注射，E组为16 μL细胞注射加MP和口服碳酸锂（750 mg/d），一个疗程6周。受试者进行3~6个月的强化步行训练，以美国脊髓损伤协会（ASIA）为主要评分指标，脊髓损伤步行指数（WISCI）和脊髓独立量表（SCIM）为次要评分指标。

结果

20例受试者的SCI平面分别位于C3~T11，平均受伤7年。治疗前，16例（80%）患者行走<10 m，18例（90%）患者自理生活需要协助。治疗后41~87周，受试者ASIA运动评分无明显变化，而WISCI和SCIM评分明显提高。15例（75%）患者可在辅助下步行10 m，12例（60%）患者恢复膀胱和肠道控制，5例（25%）患者由完全性SCI变为不完全性SCI；所有患者无神经功能丢失。

结论

UCBMC移植和步行训练能提高慢性完全性SCI患者的WISCI和SCIM评分，但对运动评分没有改善，因此推测UCMBC移植能促进轴突的生长，从而激活中枢模式发生器，改善运动、排尿和排便等功能，而且联合使用MP和碳酸锂对细胞移植治疗无明显作用。

关键词: 脊髓损伤, 脐血单核细胞, 移植

Objective

To assessing the safety, feasibility, efficacy and optimal cell dose of human leukocyte antigen (HLA≥4∶6) matched umbilical cord blood mononuclear cells (UCBMC) in the therapy of chronic complete spinal cord injury (SCI), and the effect of combined use of methylprednisolone (MP) and lithium carbonate on cell transplantation.

Methods

Twenty patients with SCI admitted to Department of Neurosurgery of 920 Hospital of Joint Logistics Support Force from February 2011 to January 2014 were selected and divided into 5 groups (group A, B, C, D, E) according to the random number table method, with 4 subjects in each group. UCBMC was injected at 4 points (2 points in each side) at the upper and lower edge of the injured spinal nerve. Group A, group B and group C were injected with 4, 8 and 16 μL (100 000 UCBMC/μL, 6.4 million cells) to the upper and lower dorsal root of SCI, group D received 16 μL cell injection plus 30 mg/kg MP intravenous injection, group E received 16 μL cell injection plus MP and 6-week oral lithium carbonate (750 mg/d). The subjects underwent intensive walking training for 3-6 months. The primary outcome was American Spinal Injury Association (ASIA) scores. Secondary outcomes include walking index of spinal cord injury (WISCI) and spinal cord independence measure (SCIM).

Results

Twenty subjects averaged 7 years after C3-T11 SCI. Before treatment, 16 subjects (80%) could not walk 10 m even with assistance, and 18 subjects (90%) need assistance for bladder or bowel care. At 41-87 weeks, ASIA motor scores did not change but WISCI and SCIM scores improved. Fifteen subjects (75%) could walk 10 m with assistance, 12 subjects (60%) did not need assistance for bladder care or bowel care, 5 subjects converted from complete to incomplete. Meanwhile none of subjects lost further neurological functions.

Conclusion

UCBMC and locomotor training improved WISCI and SCIM but not motor scores. We hypothesize that UCMBC transplants stimulate growth of axons that activate central pattern generators for locomotion, micturition, and defecation. Combined use of MP and lithium carbonate had no obvious effect on cell transplantation.

Key words: Spinal cord injury, Umbilical cord blood mononuclear cell, Transplantation

图1 显微镜下行脐血单核细胞注射（箭头示进针点）

表1 各组治疗前后疼痛模拟视觉量表评分变化

组别	治疗前（0周）	治疗后41~87周
A组	12	7
B组	9	15
C组	21	20
D组	0	69
E组	72	13

表1 各组治疗前后疼痛模拟视觉量表评分变化

组别	治疗前（0周）	治疗后41~87周
A组	12	7
B组	9	15
C组	21	20
D组	0	69
E组	72	13

图2 脊髓损伤患者治疗前后KLS分级及WISCI评分结果

表2 各组治疗前后脊髓独立量表总分（均数）变化统计

组别	治疗前（0周）	治疗后41~87周	差值
A组	41.75	59.75	18.00
B组	44.75	57.50	12.75
C组	43.75	62.25	18.50
D组	36.25	65.25	29.00
E组	41.25	58.50	17.25

表2 各组治疗前后脊髓独立量表总分（均数）变化统计

组别	治疗前（0周）	治疗后41~87周	差值
A组	41.75	59.75	18.00
B组	44.75	57.50	12.75
C组	43.75	62.25	18.50
D组	36.25	65.25	29.00
E组	41.25	58.50	17.25

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