Human beta-globin gene locus (HBB locus) (HBB locus)

The human beta-globin (HBB) gene locus, located on chromosome 11p15.4, is a complex genomic region containing a cluster of genes (HBE1, HBG2, HBG1, HBD, and HBB) that encode the beta-like subunits of hemoglobin (NCBI Gene ID: 3043). These genes are expressed in a developmentally regulated manner, with HBB encoding the adult beta-globin chain essential for the formation of Hemoglobin A (HbA) (UniProt P68871). Mutations in the HBB gene lead to severe hemoglobinopathies, such as sickle cell disease and various forms of beta-thalassemia, characterized by defective or absent beta-globin production (StatPearls: Sickle Cell Anemia). In autologous hematopoietic stem cell (HSC) therapies, the HBB locus is the primary target for genetic intervention to restore normal erythropoiesis. Current therapeutic approaches include the use of lentiviral vectors, such as in betibeglogene autotemcel (Zynteglo) and lovotibeglogene autotemcel (Lyfgenia), to integrate a functional HBB gene into the patient's HSCs (FDA: Zynteglo; FDA: Lyfgenia). These modified cells are then re-infused into the patient after myeloablative conditioning, allowing for the production of functional hemoglobin and reducing or eliminating the need for chronic blood transfusions (NEJM: Kanter et al., 2022). Additionally, genome editing technologies like CRISPR/Cas9 are being explored to directly correct mutations within the HBB locus or to disrupt regulatory elements that suppress fetal hemoglobin production (Nature Medicine: Frangoul et al., 2021). This target represents a paradigm shift in treating inherited blood disorders by addressing the underlying genetic cause within the patient's own stem cell population.

Other names

Beta-globin clusterHBB clusterHemoglobin subunit beta locus11p15.4 locusBeta-globin gene complex

Ex vivo lentiviral-mediated gene addition of a functional or modified beta-globin gene into autologous hematopoietic stem cells to restore production of functional hemoglobin (FDA: Zynteglo; NEJM: Thompson et al., 2018).