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Editing a y-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype

Abstract : Sickle cell disease (SCD) is caused by a single amino acid change in the adult hemoglobin (Hb)  chain that causes Hb polymerization and red blood cell (RBC) sickling. The co-inheritance of mutations causing fetal -globin production in adult life hereditary persistence of fetal Hb (HPFH) reduces the clinical severity of SCD. HPFH mutations in the HBG -globin promoters disrupt binding sites for the repressors BCL11A and LRF. We used CRISPR-Cas9 to mimic HPFH mutations in the HBG promoters by generating insertions and deletions, leading to disruption of known and putative repressor binding sites. Editing of the LRF-binding site in patient-derived hematopoietic stem/progenitor cells (HSPCs) resulted in -globin derepression and correction of the sickling phenotype. Xenotransplantation of HSPCs treated with gRNAs targeting the LRF-binding site showed a high editing efficiency in repopulating HSPCs. This study identifies the LRF-binding site as a potent target for genome-editing treatment of SCD.
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https://hal-mnhn.archives-ouvertes.fr/mnhn-03100446
Contributor : Carine Giovannangeli <>
Submitted on : Wednesday, January 6, 2021 - 4:14:11 PM
Last modification on : Wednesday, April 28, 2021 - 2:02:01 PM

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Leslie Weber, Giacomo Frati, Tristan Felix, Giulia Hardouin, Antonio Casini, et al.. Editing a y-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Science Advances , American Association for the Advancement of Science (AAAS), 2020, 6 (7), pp.eaay9392. ⟨10.1126/sciadv.aay9392⟩. ⟨mnhn-03100446⟩

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