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CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia

List of authors.
  • 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.

Summary

The safety of CRISPR (clustered regularly interspaced short palindromic repeats)–based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing–related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.)

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Funding and Disclosures

Supported by grants from the Beijing Municipal Science and Technology Commission (D171100000517004), the National Key Research and Development Program of China (2017YFA0103000), the Science and Technology Planning Project of Beijing City (Z181100001818004), and the National 13th Five-Year Grand Program on Key Infectious Disease Control (2017ZX10202102-005-003 and 2017ZX10202101-004-001).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. L. Xu, Dr. J. Wang, Mr. Y. Liu, and Mr. L. Xie and Drs. H. Wu, H. Deng, and H. Chen contributed equally to this article.

This article was published on September 11, 2019, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank Zeyu Chen, Shicheng Sun, Chengyan Wang, Weifeng Lai, and Shunyi Liao for assistance with the experiment design and with revising an earlier version of the manuscript; Edouard Stanley and Tung-Tien Sun for assistance with revising an earlier version of the manuscript; Yang Gao, Yang Liu, Huangfan Xie, Hanwei Li, Jingyi Wei, Kailong Xia, Cui Zhang, Qiang Shi, Guoliang Hu, Xiaoyue Gao, and Xuanling Shi for technical assistance; and Jing Zhang, Min Jiang, Yongfeng Su, Na Liu, Xiao Lou, Yizhi Wang, Ying Sun, and Yafei Wang, of the 307 Hospital of the People’s Liberation Army, for contributions to the care of the patient.

Author Affiliations

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 .

Hu Chen, M.D., Ph.D., is deceased.

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