Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs

doi:10.1016/j.stem.2023.10.007

KMS > 免疫化学研究所

	Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs
	Han, Wenyan1 ; Qiu, Hou-Yuan 2; Sun, Shangwu1,3 ; Fu, Zhi-Can 4,5; Wang, Guo-Quan 2; Qian, Xiaowen 6; Wang, Lijie 7; Zhai, Xiaowen 6; Wei, Jia 5; Wang, Yichuan 7; Guo, Yi-Lin 5; Cao, Guo-Hua 2; Ji, Rui-Jin 2; Zhang, Yi-Zhou 2; Ma, Hongxia 7; Wang, Hongsheng 6; Zhao, Mingli1 ; Wu, Jing1 ; Bi, Lili 2; Chen, Qiu-Bing 2; Li, Zifeng 6; Yu, Ling 6; Mou, Xiaodun 7; Yin, Hao 2,8,9,12; Yang, Li 5; Chen, Jia1,10,11 ; Yang, Bei1,3,10 ; Zhang, Ying 2,12
	2023-11
发表期刊	CELL STEM CELL (IF:19.8[JCR-2023],22.6[5-Year])
ISSN	1875-9777
发表状态	已发表
DOI	10.1016/j.stem.2023.10.007
摘要	Reactivating silenced γ-globin expression through disruption of repressive regulatory domains offers a therapeutic strategy for treating β-hemoglobinopathies. Here, we used transformer base editor (tBE), a recently developed cytosine base editor with no detectable off-target mutations, to disrupt transcription factor binding motifs in hematopoietic stem cells. By performing functional screening of six motifs with tBE, we found that directly disrupting the BCL11A binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparison with other clinical and preclinical strategies using Cas9 nuclease or conventional BEs (ABE8e and hA3A-BE3), we found tBE-meditated disruption of BCL11A binding motif at HBG1/2 promoter triggered the highest fetal hemoglobin in healthy and β-thalassemia patient hematopoietic stem/progenitor cells, meanwhile exhibiting no detectable DNA or RNA off-target mutations. Durable therapeutic editing by tBE persisted in repopulating hematopoietic stem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating β-hemoglobinopathies.
收录类别	SCI
语种	英语
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/345970
专题	免疫化学研究所生命科学与技术学院生命科学与技术学院_PI研究组_陈佳组生命科学与技术学院_硕士生生命科学与技术学院_博士生免疫化学研究所_PI研究组_杨贝组
共同第一作者	Qiu, Hou-Yuan; Sun, Shangwu; Fu, Zhi-Can; Wang, Guo-Quan; Qian, Xiaowen
通讯作者	Yang, Li; Chen, Jia; Yang, Bei; Zhang, Ying
作者单位	1.Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China 2.Department of Rheumatology and Immunology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China 3.Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China 4.Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China 5.Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. 6.Department of Hematology and Oncology, Children's Hospital of Fudan University, Shanghai, 201102, China. 7.CorrectSequence Therapeutics, Shanghai, 201210, China 8.Department of Pathology and Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China 9.TaiKang Centre for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China. 10.Shanghai Clinical Research and Trial Center, Shanghai, 201210, China 11.Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine, ShanghaiTech University, Shanghai, 200031, China 12.State Key Laboratory of Virology, Wuhan University, Wuhan, China.
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院; 上海科技大学; 免疫化学研究所
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Han, Wenyan,Qiu, Hou-Yuan,Sun, Shangwu,et al. Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs[J]. CELL STEM CELL,2023.
APA	Han, Wenyan.,Qiu, Hou-Yuan.,Sun, Shangwu.,Fu, Zhi-Can.,Wang, Guo-Quan.,...&Zhang, Ying.(2023).Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs.CELL STEM CELL.
MLA	Han, Wenyan,et al."Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs".CELL STEM CELL (2023).