Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype
Leslie Weber, Giacomo Frati, Tristan Félix, Giulia Hardouin, Antonio Casini, Clara Wollenschlaeger, Vasco Meneghini, Cécile Masson, Anne De Cian, Anne Chalumeau, Fulvio Mavilio, Mario Amendola, Isabelle André‐Schmutz, Anna Cereseto, Wassim El Nemer, Jean‐Paul Concordet, Carine Giovannangeli, Marina Cavazzana, Annarita Miccio
Abstract
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.