Journal
SCIENCE ADVANCES
Volume 6, Issue 7, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aay9392
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Funding
- European Research Council (ERC-2015-AdG, GENEFORCURE)
- Agence Nationale de la Recherche [ANR-16-CE18-0004, ANR-11-INBS-0014-TEFOR, ANR-17-CE13-0016-i-MMEJ, ANR-10-IAHU-01]
- Paris Ile-de-France Region under DIM Therapie genique initiative
- Genopole (CHAIRE JUNIOR FONDAGEN)
- Agence Nationale de la Recherche (ANR) [ANR-11-INBS-0014] Funding Source: Agence Nationale de la Recherche (ANR)
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Sickle cell disease (SCD) is caused by a single amino acid change in the adult hemoglobin (Hb) beta chain that causes Hb polymerization and red blood cell (RBC) sickling. The co-inheritance of mutations causing fetal gamma-globin production in adult life hereditary persistence of fetal Hb (HPFH) reduces the clinical severity of SCD. HPFH mutations in the HBG gamma-globin promoters disrupt binding sites for the repressors BCL1 1A 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 gamma-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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