期刊
FRONTIERS IN GENETICS
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2022.881937
关键词
fetal hemoglobin (HbF); hereditary persistence of fetal hemoglobin (HPFH); thalassemia; genome editing; adeno-associated virus (AAV)
资金
- National Natural Science Foundation of China [32070582, 31872800, 82072890, 31701288]
- Natural Science Foundation of Guangdong Province [2020A1515010113]
- Guangzhou City Science and Technology Key Topics Project [201904020025]
- Guangzhou City Science and Technology Project [202102010118]
This study proposes a novel Cas9/AAV6-mediated genome editing strategy for treating beta-thalassemia. By introducing naturally occurring HPFH mutations and disrupting BCL11A binding sites in HBG1/HBG2 promoters, precise on-target editing and significantly increased gamma-globin expression were observed.
Reactivation of gamma-globin expression is a promising therapeutic approach for beta-hemoglobinopathies. Here, we propose a novel Cas9/AAV6-mediated genome editing strategy for the treatment of beta-thalassemia: Natural HPFH mutations -113A > G, -114C > T, -117G>A, -175T > C, -195C > G, and -198T > C were introduced by homologous recombination following disruption of BCL11A binding sites in HBG1/HBG2 promoters. Precise on-target editing and significantly increased gamma-globin expression during erythroid differentiation were observed in both HUDEP-2 cells and primary HSPCs from beta-thalassemia major patients. Moreover, edited HSPCs maintained the capacity for long-term hematopoietic reconstitution in B-NDG hTHPO mice. This study provides evidence of the effectiveness of introducing naturally occurring HPFH mutations as a genetic therapy for beta-thalassemia.
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