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Article Dans Une Revue Blood Année : 2018

Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus

C. Antoniani
  • Fonction : Auteur
V. Meneghini
  • Fonction : Auteur
E. Magrin
  • Fonction : Auteur
L. Weber
  • Fonction : Auteur
  • PersonId : 1000277
  • IdRef : 220196206
S. El Hoss
  • Fonction : Auteur
R. Kurita
  • Fonction : Auteur
Y. Nakamura
  • Fonction : Auteur
T. J. Cradick
  • Fonction : Auteur
A. S. Lundberg
  • Fonction : Auteur
M. Porteus
  • Fonction : Auteur
W. El Nemer
M. Cavazzana
  • Fonction : Auteur
F. Mavilio

Résumé

Naturally occurring, large deletions in the beta-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and beta-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the delta- and beta-globin genes and a putative gamma-delta intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in gamma-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the beta-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of gamma-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of beta-hemoglobinopathies.

Dates et versions

hal-02880783 , version 1 (25-06-2020)

Identifiants

Citer

C. Antoniani, V. Meneghini, A. Lattanzi, T. Felix, O. Romano, et al.. Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus. Blood, 2018, 131, pp.1960-1973. ⟨10.1182/blood-2017-10-811505⟩. ⟨hal-02880783⟩
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