Abstract
Gene therapy using lentiviral vectors offers a promising alternative treatment for β-thalassemia, a common monogenic blood disorder. Although the BB305 vector has demonstrated long-term clinical success-enabling most β-thalassemia patients to become transfusion-independent and substantially reducing vaso-occlusive events in sickle cell disease-there remains a significant opportunity to enhance its efficacy and lower production costs. Here, we present G2B, a novel hemoglobin beta gene (HBB) lentiviral vector derived from BB305-like constructs (BB305L), engineered by shortening the locus control region (LCR) and incorporating a mutated HBG2 promoter. Compared to BB305L, G2B achieves a ~4-fold increase in lentiviral titer and a 60% boost in β-globin expression. In a transplantation model using Hbbth4/Hbb+ hematopoietic stem/progenitor cells, G2B demonstrates robust therapeutic efficacy without compromising integration safety. These findings suggest that G2B may offer a more potent, efficient, and potentially cost-effective gene therapy option for β-thalassemia and other hemoglobinopathies.
Keywords:
Gene therapy; Hemoglobin subunit beta (HBB); Hemoglobinopathies; Integration safety; Lentiviral vector; Locus control region; β-Thalassemia.