Editing a y-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype - Archive ouverte HAL Access content directly
Journal Articles Science Advances Year : 2020

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

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Leslie Weber
  • Function : Author
Giacomo Frati
Tristan Felix
  • Function : Author
Giulia Hardouin
  • Function : Author
Antonio Casini
  • Function : Author
Clara Wollenschlaeger
  • Function : Author
Vasco Meneghini
  • Function : Author
Cecile Masson
  • Function : Author
Anne de Cian
  • Function : Author
Anne Chalumeau
  • Function : Author
Fulvio Mavilio
  • Function : Author
Mario Amendola
Isabelle Andre-Schmutz
Anna Cereseto
  • Function : Author
Wassim El Nemer
Jean-Paul Concordet
  • Function : Author
Marina Cavazzana
Annarita Miccio
  • Function : Author

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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Dates and versions

mnhn-03100446 , version 1 (06-01-2021)

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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 , 2020, 6 (7), pp.eaay9392. ⟨10.1126/sciadv.aay9392⟩. ⟨mnhn-03100446⟩
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