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Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

Abstract : Abstract 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.
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https://hal-mnhn.archives-ouvertes.fr/mnhn-03868573
Contributor : Carine Giovannangeli Connect in order to contact the contributor
Submitted on : Wednesday, November 23, 2022 - 8:07:59 PM
Last modification on : Saturday, November 26, 2022 - 3:25:29 AM

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Panagiotis Antoniou, Giulia Hardouin, Pierre Martinucci, Giacomo Frati, Tristan Felix, et al.. Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression. Nature Communications, 2022, 13 (1), pp.6618. ⟨10.1038/s41467-022-34493-1⟩. ⟨mnhn-03868573⟩

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