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

Blood, 2018-04, Vol.131 (17), p.1960-1973 [Peer Reviewed Journal]

Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 0006-4971 ;EISSN: 1528-0020 ;DOI: 10.1182/blood-2017-10-811505

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  • Title:
    Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human b-globin locus
  • Author: Antoniani, Chiara ; Meneghini, Vasco ; Lattanzi, Annalisa ; Felix, Tristan ; Romano, Oriana ; Magrin, Elisa ; Weber, Leslie ; Pavani, Giulia ; El Hoss, Sara ; Kurita, Ryo ; Nakamura, Yukio ; Cradick, Thomas ; Lundberg, Ante ; Porteus, Matthew ; Amendola, Mario ; El Nemer, Wassim ; Cavazzana, Marina ; Mavilio, Fulvio ; Miccio, Annarita
  • Subjects: Life Sciences
  • Is Part Of: Blood, 2018-04, Vol.131 (17), p.1960-1973
  • Description: CRISPR/Cas9mediated disruption of the b-globin locus architecture reactivates fetal g-globin expression in adult erythroblasts. l Fetal g-globin reactivation and sickle b-globin downregulation leads to the amelioration of the SCD cell phenotype. Naturally occurring, large deletions in the b-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and b-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 dand b-globin genes and a putative g-d intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in g-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 b-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of g-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 b-hemoglobinopathies.
  • Publisher: American Society of Hematology
  • Language: English
  • Identifier: ISSN: 0006-4971
    EISSN: 1528-0020
    DOI: 10.1182/blood-2017-10-811505
  • Source: Hyper Article en Ligne (HAL) (Open Access)
    GFMER Free Medical Journals
    Alma/SFX Local Collection
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