| Autor: |
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 |
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| Zdroj: |
Nature Communications; 11/4/2022, Vol. 13 Issue 1, p1-22, 22p |
| Abstrakt: |
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. Antoniou and colleagues used base editing to generate a variety of mutations inducing γ-globin and rescue the β-hemoglobinopathy phenotype. This strategy was safe and effective in long-term repopulating hematopoietic stem/progenitor cells. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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