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Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
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Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
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Journal Article
Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
2022
Overview
Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the
HBG
transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the −200 region of the
HBG
promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy – even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of
HBG
promoters is a safe, universal strategy for treating β-hemoglobinopathies.
Antoniou and colleagues used base editing to generate a variety of mutations inducing γ-globin and rescue the β-hemoglobinopathy phenotype. This strategy was safe and effective in long-term repopulating hematopoietic stem/progenitor cells.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/31
/ 38
/ 38/15
/ 38/91
/ 42/109
/ 42/41
/ 42/70
/ 64
/ Anemia, Sickle Cell - genetics
/ Biochemistry, Molecular Biology
/ Editing
/ Fetal Hemoglobin - metabolism
/ Fetuses
/ Hematopoietic Stem Cells - metabolism
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ Nuclease
/ Science
/ Stems
