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CRISPR编辑干细胞治疗一例HIV感染合并急性淋巴细胞白血病患者
CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia


Lei Xu ... 肿瘤 • 2019.09.26
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摘要


基于CRISPR(成簇的规律间隔的短回文重复序列)的基因组编辑在人类基因治疗背景下的安全性仍基本未知。因为不表达CCR5CCR5-null)的血细胞基本上可以抵抗HIV-1进入,因此对于人类免疫缺陷病毒1型(HIV-1)感染,CCR5是合理但并非具有绝对保护作用的靶点。我们将CRISPR编辑的CCR5敲除造血干细胞和祖细胞移植到一例HIV-1感染合并急性淋巴细胞白血病患者体内。患者的急性淋巴细胞白血病处于完全缓解期,达到完全供者细胞嵌合,并且CCR5敲除的供者细胞持续存在19个月以上,且并未发生与基因编辑相关的不良事件。CCR5敲除的CD4+细胞百分比在抗逆转录病毒治疗中断期间略有增加。尽管我们实施了成功移植且CRISPR编辑的HSPC实现了长期植入,但淋巴细胞中的CCR5破坏百分比只有约5%,因而表明我们需要对这一方法进行进一步研究(由北京市科学技术委员会等资助,在ClinicalTrials.gov注册号为NCT03164135)。

CRISPR–Cas9(成簇的规律间隔的短回文重复序列[CRISPR]–CRISPR相关蛋白9 [Cas9])技术已被广泛用于体外编辑哺乳动物细胞的基因组1-4。虽然该方法显示出潜在临床用途,并且已经启动临床试验来探索基于CRISPR的疗法的安全性和可行性(例如ClinicalTrials.gov注册号NCT03655678和NCT03399448),但是这些试验的结果尚未发表5

目前已经证明,将天然存在CCR5突变的造血干细胞和祖细胞(HSPC)进行异基因移植后,可以实现人类免疫缺陷病毒1型(HIV-1)的长期清除,因为CCR5是HIV进入细胞的关键辅助受体6-9。这些例子提出了以下可能性,用人工破坏CCR5的细胞进行移植可能是使细胞对HIV-1感染产生抗性的另一种方法。在之前的一项研究中,我们建立了能够以27%的效率在人类HSPC内破坏CCR5,且不含有病毒的CRISPR基因组编辑系统10。在一个动物模型中,这些CCR5修饰的HSPC稳健地生成了对HIV-1感染具有抗性的人类免疫系统。我们在本文中报告了采用CCR5编辑的HSPC对患急性淋巴细胞白血病的一例HIV-1感染患者进行的异基因移植。





作者信息

Lei Xu, M.D., Ph.D., Jun Wang, M.D., Ph.D., Yulin Liu, B.S., Liangfu Xie, B.S., Bin Su, Ph.D., Danlei Mou, M.D., Ph.D., Longteng Wang, B.S., Tingting Liu, M.D., Xiaobao Wang, B.S., Bin Zhang, M.D., Ph.D., Long Zhao, Ph.D., Liangding Hu, M.D., Hongmei Ning, M.D., Ph.D., Yufeng Zhang, B.S., Kai Deng, Ph.D., Lifeng Liu, Ph.D., Xiaofan Lu, Ph.D., Tong Zhang, M.D., Ph.D., Jun Xu, Ph.D., Cheng Li, Ph.D., Hao Wu, M.D., Hongkui Deng, Ph.D., and Hu Chen, M.D., Ph.D.
From the Department of Hematopoietic Stem Cell Transplantation (L. Xu, J.W., T.L., B.Z., L.H., H.N., Y.Z., H.C.) and the Cell and Gene Therapy Center (B.Z., L.Z., L.H., H.C.), 307 Hospital of the People’s Liberation Army, the Fifth Medical Center of the People’s Liberation Army General Hospital, the Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, and the Ministry of Education (MOE) Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking–Tsinghua Center for Life Sciences (Y.L., L. Xie, X.W., J.X., H.D.), and the School of Life Sciences, Center for Statistical Science and Center for Bioinformatics (L.W., C.L.), Peking University, and the Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing Key Laboratory for HIV–AIDS Research (B.S., D.M., L.L., X.L., T.Z., H.W.), Beijing, and the Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou (K.D.) — all in China. Address reprint requests to Dr. H. Deng at the Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking–Tsinghua Center for Life Sciences, Peking University, No. 5, Yiheyuan Rd., Beijing 100871, China, or at hongkui_deng@pku.edu.cn. Hu Chen, M.D., Ph.D., is deceased.

 

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