β-thalassemia is a common inherited hemoglobin disorder caused by reduced or absent β-globin production, leading to ineffective erythropoiesis, chronic anemia, and, in severe cases, lifelong transfusion dependence. Although allogeneic hematopoietic stem cell transplantation can be curative, its use is limited by donor availability and transplant-related complications. In recent years, gene therapy has emerged as a promising alternative and has rapidly changed the treatment landscape for β-thalassemia. In this review, we summarize both established and emerging gene-based strategies, including lentiviral gene addition to restore HBB expression and gene editing approaches aimed at reactivating fetal hemoglobin. We discuss key targets such as the erythroid-specific BCL11A enhancer, repressor-binding sites in the HBG promoters, and other regulatory elements involved in globin switching. We also highlight the growing potential of newer technologies such as base editing and prime editing, which may offer greater precision and reduce the risks associated with double-strand DNA breaks. Finally, we address the major challenges that still need to be resolved, including safety, durability, technical complexity, and access to treatment. Overall, gene therapy is moving β-thalassemia closer to a broadly applicable curative approach.
Liang et al. (Thu,) studied this question.