Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs
Copyright © 2023 Elsevier Inc. All rights reserved..
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 disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and β-thalassemia patient hematopoietic stem/progenitor cells while 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Cell stem cell - 30(2023), 12 vom: 07. Dez., Seite 1624-1639.e8 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Han, Wenyan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.stem.2023.10.007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and β-thalassemia patient hematopoietic stem/progenitor cells while 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a hematopoietic stem cell | |
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| 700 | 1 | |a Qiu, Hou-Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shangwu |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Zhi-Can |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guo-Quan |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Xiaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lijie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhai, Xiaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yichuan |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yi-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Guo-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Rui-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yi-Zhou |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Hongxia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hongsheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Mingli |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Bi, Lili |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Qiu-Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zifeng |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Mou, Xiaodun |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
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