Hemoglobin subunit gamma G16D (HbF-G16D)

Hemoglobin subunit gamma G16D is an engineered variant of the human fetal hemoglobin gamma chain (primarily HBG1) developed as a therapeutic agent for sickle cell disease and beta-thalassemia [1, 6]. This variant features a glycine-to-aspartic acid substitution at position 16 (G16D), a modification modeled after the naturally occurring, high-affinity beta-globin variant Hemoglobin J-Baltimore [14]. The G16D mutation increases the electrostatic affinity of the gamma-globin chain for alpha-globin subunits, enabling the preferential formation of fetal hemoglobin (HbF) tetramers over sickle hemoglobin (HbS) tetramers [6, 9]. In clinical applications, such as the gene therapy ARU-1801 (formerly CSL200), a lentiviral vector is used to deliver the G16D-modified gamma-globin gene into autologous hematopoietic stem cells [1, 6]. The resulting HbF-G16D protein acts as a potent anti-sickling agent by inhibiting the polymerization of HbS, thereby reducing the incidence of vaso-occlusive crises and other disease complications [6, 9]. This approach is often paired with reduced-intensity conditioning to improve the safety profile compared to traditional myeloablative gene therapies [6].

Other names

gamma-globin G16DHbF-G16DGbGMARU-1801CSL200Hemoglobin subunit gamma-1 G16DHemoglobin subunit gamma-2 G16D

Lentiviral-mediated gene addition to express a modified gamma-globin that forms a high-affinity anti-sickling fetal hemoglobin (HbF-G16D), which inhibits the polymerization of sickle hemoglobin (HbS).