人脐带间充质干细胞的安全性毒理学评价

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英文篇名：Safety and toxicological evaluation of human umbilical cord mesenchymal stem cells 作者：田义超 ; 周端鹏 ; 崔艳君 ; 张亚奇 ; 刘梦杰 ; 饶巍 ; 张权 ; 方攀 ; 庞聪 ; 岑玉杰 ; 韩兵 ; 武栋成 英文作者：TIAN Yi-chao;ZHOU Duan-peng;CUI Yan-jun;ZHANG Ya-qi;LIU Meng-jie;RAO Wei;ZHANG Quan;FANG Pan;PANG Cong;CEN Yu-jie;HAN Bing;WU Dong-cheng;Hubei Topgene Biotechnology Co.,Ltd.,Wuhan Branch;Wuhan Hamilton Biotechnology Co.,Ltd.;Wuhan University Medical School; 关键词：脐带间充质干细胞 ; 溶血 ; 异常毒性 ; 过敏 ; 致瘤性 ; 单次给药毒性 ; 安全性 英文关键词：mesenchymal stem cells;;hemolytic;;abnormal toxicity;;anaphylaxis;;tumorigenicity;;single dose toxicity;;safety 中文刊名：ZXYZ 英文刊名：Chinese Journal of New Drugs 机构：湖北天勤生物科技有限公司武汉分公司;武汉汉密顿生物科技股份有限公司;武汉大学基础医学院; 出版日期：2019-01-30 出版单位：中国新药杂志 年：2019 期：v.28 语种：中文; 页：ZXYZ201902006 页数：5 CN：02 ISSN：11-2850/R 分类号：35-39

摘要

目的:评价人脐带间充质干细胞的安全性,为临床安全用药提供依据。方法:通过家兔体外溶血试验、小鼠和豚鼠异常毒性试验、豚鼠主动全身过敏试验、裸鼠致瘤性试验、小鼠和食蟹猴单次给药毒性试验,评价人脐带间充质干细胞的安全性。结果:人脐带间充质干细胞无明显溶血反应,无异常毒性,无致敏性,无致瘤性。人脐带间充质干细胞对小鼠静脉注射给药的最大耐受量(MTD)> 2. 0×107cells·kg~(-1)。对食蟹猴单次静脉滴注给药的近似致死剂量> 10. 0×107cells·kg~(-1),无毒反应剂量为2. 0×107cells·kg~(-1)。结论:试验结果表明,人脐带间充质干细胞安全、毒性低,且无溶血和过敏反应。
        Objective: To provide preclinical safety evidence of human umbilical cord mesenchymal stem cells. Methods: The safety of human umbilical cord mesenchymal stem cells was evaluated by testing of hemolysis with rabbit blood,abnormal toxicity in mouse and guinea pig,active systemic anaphylaxis in guinea pig,tumorigenicity in nude mouse,single dose toxicity in mouse and cynomolgus monkey,respectively. Results: Human umbilical cord mesenchymal stem cells had no hemolytic effect on rabbit blood. There was no sign of abnormal toxicity,allergy,tumorigenicity as well as acute toxicity in the animals after administration of the stem cells. When human umbilical cord mesenchymal stem cells were intravenously administered,the maximum tolerance dose in mouse was > 2. 0 ×107 cells·kg-1; the lethal dose and the NOAEL in cynomolgus monkey were > 10. 0 × 107 cells·kg-1 and 2. 0 × 107 cells·kg-1,respectively. Conclusion: Human umbilical cord mesenchymal stem cells have no toxic effects at tested doses,thus are safe for the animals and may be applied in clinical therapy.

引文

[1]宋征,马璟.干细胞制剂临床前安全评价方法[J].中国新药杂志,2013,22(22):2611-2615.
    [2]李嘉,尹春艳.人脐带间充质干细胞在临床治疗中的研究进展[J].医学综述,2016,10(22):1931-1934.
    [3]崔国宁,刘喜平.骨髓间充质干细胞治疗炎症性肠病研究进展[J].今日药学,2018,28(10):9.
    [4] MABED M,SHAHIN M. Mesenchymal stem cell-based therapy for the treatment of type 1 diabetes mellitus[J]. Curr Stem Cell Res Ther,2012,7(3):179-190.
    [5] KIRANA S,STRATMANN B,PRANTE C,et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients[J]. Int J Clin Pract,2012,66(4):384-393.
    [6] LAI RC,CHEN TS,LIM SK. Mesenchymal stem cell exosome:a novel stem cell-based therapy for cardiovascular disease[J].Regen Med,2011,6(4):481-492.
    [7]陈云,邹宜諠,张晓慧,等.韩国与日本干细胞药品审批、监管及对我国的启示[J].中国新药杂志,2018,27(3):267-272.
    [8] DOMINICI M,BLANC KL,MUELLER I,et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement[J]. Cytotherapy,2006,8(4):315-317.
    [9]国家药典委员会.中华人民共和国药典.异常毒性检查法[S]. 2015年版.第四部.北京:中国医药科技出版社,2015:通则1141.
    [10]国家药品监督管理局.细胞治疗产品研究与评价技术指导原则(试行)[EB/OL].[2018-03-09]. http://www. sfda.gov. cn/WS01/CL0087/220082. html.
    [11]国家药品监督管理局.干细胞制剂质量控制及临床前研究指导原则(试行)[EB/OL].[2018-03-09]. http://www. sfda. gov. cn/WS01/CL1616/127242. html.
    [12]王冠华,荆宝琴,高畅,等.间充质干细胞的毒性作用研究[J].中国临床药理学杂志,2015,31(16):1645-1647.
    [13]海泉,陈烽烽,周诚,等.脐带间充质干细胞临床前安全性考察[J].四川医学,2016,37(3):237-241.
    [14] BONGSO A,FONG CY. The therapeutic,challenges and fulture clinical directions of stem from the Wharton's Jelly of the human umbilical cord[J]. Stem Cell Rev,2013,9(2):226-240.
    [15] NAUTA AJ,FIBBE WE. Immunomodulatory properties of mesenchymal stromal cells[J]. Blood,2007,110(10):3499-3506.