Genomic DNA at the hemoglobin subunit beta (HBB) locus and gamma-globin regulatory elements (HBB/HBG locus)

The target consists of the genomic DNA at the hemoglobin subunit beta (HBB) locus and the regulatory elements controlling gamma-globin (HBG1/HBG2) expression within autologous hematopoietic stem and progenitor cells (HSPCs). This genetic region is critical for the production of adult hemoglobin (HbA) and fetal hemoglobin (HbF), and it is the site of mutations causing beta-hemoglobinopathies such as sickle cell disease and beta-thalassemia (10, 22). In these conditions, defective or absent beta-globin leads to severe anemia and vaso-occlusive complications (1, 20). Therapeutic strategies targeting this locus aim to restore functional hemoglobin production by either inserting a healthy HBB gene or reactivating the developmentally silenced gamma-globin genes to produce HbF (14, 18). Drugs like exagamglogene autotemcel use CRISPR/Cas9 to disrupt the BCL11A erythroid-specific enhancer, thereby inducing HbF, while others like lovotibeglogene autotemcel utilize lentiviral vectors to add a functional globin transgene (2, 4, 15). These ex vivo modifications are performed on the patient's own stem cells, which are then reinfused to provide a long-term, potentially curative treatment by populating the erythroid lineage with cells capable of producing non-sickling or functional hemoglobin (5, 6, 11).

Other names

Beta-globin gene locusHBG1/HBG2 regulatory elementsBCL11A erythroid enhancerHemoglobin subunit beta locusHBB/HBG1/HBG2 gene clusterFetal hemoglobin regulatory elements

CRISPR/Cas9-mediated disruption of the BCL11A erythroid-specific enhancer to induce fetal hemoglobin expression; Lentiviral-mediated gene addition of a functional or modified HBB transgene into hematopoietic stem cells.