期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 10, 期 -, 页码 313-326出版社
CELL PRESS
DOI: 10.1016/j.omtm.2018.08.003
关键词
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资金
- NIH [R01-DK101328-01A1]
- Cooley's Anemia Foundation
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK101328, U54DK106829] Funding Source: NIH RePORTER
In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11 a to upregulate the expression of gamma-globin (fetal hemoglobin). In these cells, disruption of the erythroid-specific enhancer of the BCL11A gene increased endogenous gamma-globin expression to levels that reached or exceeded those observed following knockout of the BCL11A coding region without negatively affecting survival or in vivo long-term proliferation of edited HSPCs and other lineages. In addition, BCL11A enhancer modification in mobilized CD34+ cells from patients with beta-thalassemia major resulted in a readily detectable gamma-globin increase with a preferential increase in G-gamma, leading to an improved phenotype and, likely, a survival advantage for maturing erythroid cells after editing. Furthermore, we documented that both normal and beta-thalassemia HSPCs not only can be efficiently expanded ex vivo after editing but can also be successfully edited post-expansion, resulting in enhanced early in vivo engraftment compared with unexpanded cells. Overall, this work highlights a novel and effective treatment strategy for correcting the beta-thalassemia phenotype by genome editing.
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