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

Cell Stem Cell. 2023-12; 
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
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摘要

Reactivating silenced γ-globin expression through the 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 that tBE-mediated dis... More

关键词

BCL11A binding site; HBG 1/2 promoter; hematopoietic stem cell; off-target mutation; transformer base editor; β-hemoglobinopathies; γ-globin reactivation.