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Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype.
- Source :
-
Science advances [Sci Adv] 2020 Feb 12; Vol. 6 (7). Date of Electronic Publication: 2020 Feb 12 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- Sickle cell disease (SCD) is caused by a single amino acid change in the adult hemoglobin (Hb) β chain that causes Hb polymerization and red blood cell (RBC) sickling. The co-inheritance of mutations causing fetal γ-globin production in adult life hereditary persistence of fetal Hb (HPFH) reduces the clinical severity of SCD. HPFH mutations in the HBG γ-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 γ-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.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Subjects :
- Binding Sites
CRISPR-Cas Systems
Fetal Hemoglobin genetics
Fetal Hemoglobin metabolism
Gene Editing methods
Humans
Phenotype
beta-Globins genetics
beta-Globins metabolism
gamma-Globins genetics
gamma-Globins metabolism
Anemia, Sickle Cell genetics
Anemia, Sickle Cell therapy
beta-Thalassemia genetics
beta-Thalassemia metabolism
beta-Thalassemia therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 6
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 32917636
- Full Text :
- https://doi.org/10.1126/sciadv.aay9392