小柯机器人

武汉大学Ying Zhang，上海科技大学Bei Yang，Jia Chen以及复旦大学Li Yang共同合作，近期取得重要工作进展。他们研究发现，对HBG启动子进行碱基编辑可诱导人造血干细胞中胎儿血红蛋白的高效表达且未检测到脱靶突变。相关研究成果2023年11月20日在线发表于《细胞—干细胞》杂志上。

据介绍，通过破坏抑制性调控结构域来激活沉默的γ-珠蛋白表达，为治疗β-血红蛋白病提供了一种治疗策略。

研究人员使用tBE（transformer base editor）工具（一种最近开发的胞嘧啶碱基编辑器，没有可检测的脱靶突变）来破坏造血干细胞中的转录因子结合基序。通过用tBE对六个基序进行功能筛选，研究人员发现直接破坏HBG1/2启动子中的BCL11A结合基序会触发最高的γ-珠蛋白表达。通过与使用Cas9核酸酶或常规BE（ABE8e和hA3A-BE3）的其它临床和临床前策略的比较，研究人员发现tBE介导的HBG1/2启动子处BCL11A结合基序的破坏在健康和β-地中海贫血患者的造血干/祖细胞中触发了最高的胎儿血红蛋白，同时没有表现出可检测的DNA或RNA脱靶突变。tBE的持久治疗性编辑在造血干细胞的再增殖中持续存在，表明tBE介导的HBG1/2启动子编辑是治疗β-血红蛋白病的安全有效策略。

附：英文原文

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

Author: Wenyan Han, Hou-Yuan Qiu, Shangwu Sun, Zhi-Can Fu, Guo-Quan Wang, Xiaowen Qian, Lijie Wang, Xiaowen Zhai, Jia Wei, Yichuan Wang, Yi-Lin Guo, Guo-Hua Cao, Rui-Jin Ji, Yi-Zhou Zhang, Hongxia Ma, Hongsheng Wang, Mingli Zhao, Jing Wu, Lili Bi, Qiu-Bing Chen, Zifeng Li, Ling Yu, Xiaodun Mou, Hao Yin, Li Yang, Jia Chen, Bei Yang, Ying Zhang

Issue&Volume: 2023-11-20

Abstract: Reactivating silenced γ-globin expression through the disruption of repressive regulatorydomains offers a therapeutic strategy for treating β-hemoglobinopathies. Here, weused transformer base editor (tBE), a recently developed cytosine base editor withno detectable off-target mutations, to disrupt transcription-factor-binding motifsin hematopoietic stem cells. By performing functional screening of six motifs withtBE, we found that directly disrupting the BCL11A-binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparisonwith other clinical and preclinical strategies using Cas9 nuclease or conventionalBEs (ABE8e and hA3A-BE3), we found that tBE-mediated disruption of the BCL11A-bindingmotif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and β-thalassemia patienthematopoietic stem/progenitor cells while exhibiting no detectable DNA or RNA off-targetmutations. Durable therapeutic editing by tBE persisted in repopulating hematopoieticstem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating β-hemoglobinopathies.

DOI: 10.1016/j.stem.2023.10.007

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00369-7

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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