Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

Author:

Antoniou Panagiotis,Hardouin Giulia,Martinucci Pierre,Frati Giacomo,Felix Tristan,Chalumeau AnneORCID,Fontana Letizia,Martin Jeanne,Masson Cecile,Brusson Megane,Maule GiuliaORCID,Rosello MarionORCID,Giovannangeli Carine,Abramowski Vincent,de Villartay Jean-PierreORCID,Concordet Jean-PaulORCID,Del Bene FilippoORCID,El Nemer WassimORCID,Amendola MarioORCID,Cavazzana MarinaORCID,Cereseto AnnaORCID,Romano OrianaORCID,Miccio AnnaritaORCID

Abstract

AbstractSickle 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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