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Antoniou, Panagiotis; Hardouin, Giulia; Martinucci, Pierre; Frati, Giacomo; Felix, Tristan; Chalumeau, Anne; Fontana, Letizia; Martin, Jeanne; Masson, Cecile; Brusson, Megane; Maule, Giulia; Rosello, Marion; Giovannangeli, Carine; Abramowski, Vincent; de Villartay, Jean-Pierre; Concordet, Jean-Paul; Del Bene, Filippo; El Nemer, Wassim; Amendola, Mario; Cavazzana, Marina; Cereseto, Anna; Romano, Oriana; Miccio, Annarita
Nature communications, 11/2022, Letnik: 13, Številka: 1Journal Article
Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the -200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy - even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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