The underlying basis of β-thalassemia pathology is the diminished β-globin synthesis leading to α-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF-β ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRI-eIF2aP, Prx2, Hsp70, and PK anti-oxidant systems and inhibitors of HO-1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the γ- or β-globin gene are novel and promising experimental gene therapy approaches for β-thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying β-thalassemia in relation to the development of new therapies and an update is given both at the pre-clinical and clinical level. Am. J. Hematol. 91:1135-1145, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.