Novel Therapeutic Advances in β-Thalassemia

SIMPLE SUMMARY: Beta-thalassemia (β-thalassemia) is an autosomal recessive inherited disorder that causes decreased production of hemoglobin. Ineffective erythropoiesis and excess iron deposition are the most significant pathophysiological problems. Chronic red blood cell transfusions along with control of iron overload are the main principles of treatment. Yet, the patients have a problematic quality of life. Recently, novel therapies have emerged based on better knowledge of the pathophysiology of the disease. Aiming at ineffective erythropoiesis through the TGF-β ligand traps, such as luspatercept, has been shown to reduce the transfusion burden. Therapeutic approaches aiming at the iron metabolism mechanisms as well as the pathway of the production of erythroid cyclic guanosine monophosphate are being used in clinical trials with encouraging results. Significant improvements in the technique of hemopoietic stem cell transplantation have been accomplished, with a focus on the improvement of the conditioning regimen and the donor selection. Gene therapy has exhibited remarkable advances using lentiviral β-globin gene insertion techniques or gene editing platforms that target the suppression of γ-globin repressors. All these approaches will have a positive result in the quality of life of thalassemia patients. ABSTRACT: The main characteristic of the pathophysiology of β-thalassemia is reduced β-globin chain production. The inevitable imbalance in the α/β-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or “disease-modifying” therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of β-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or β-globin gene have entered the clinical trial setting. Agents such as TGF-β ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-β ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent β-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in β-thalassemia.