METHODS FOR INCREASING FETAL HEMOGLOBIN CONTENT IN EUKARYOTIC CELLS AND USES THEREOF FOR THE TREATMENT OF HEMOGLOBINOPATHIES

摘要

The clinical severity of β-hemoglobinopathies is alleviated by the co-inheritance of genetic mutations causing a sustained fetal γ-globin chain production at adult age, a condition termed hereditary persistence of fetal hemoglobin (HPFH). Here, the inventors have compared the extent of fetal hemoglobin (HbF) de-repression following CRISPR/Cas9-mediated targeting of different regions of the HBG1 and HBG2 promoters in an adult erythroid cell line (HUDEP-2). They achieved a potent and pancellular HbF re-activation upon disruption of binding sites for γ-globin repressors located in both HBG1 and HBG2 genes. They validated these findings in Red Blood Cells (RBCs) derived from genome edited Sickle Cell Disease (SCD) patient hematopoietic stem/progenitor cells. Overall, this study identified a binding site for an HbF repressor as a novel and potent target for the treatment of β-hemoglobinopathies. Accordingly, the present invention relates to a method for increasing fetal hemoglobin content in a eukaryotic cell comprising the step of disrupting the binding site for Leukemia/lymphoma-related factor (LRF) in the HBG1 or HBG2 promoter.