Targeting the Second Transferrin Receptor as Emerging Therapeutic Option for β-Thalassemia Major

Abstract

HemaTopicsOpen Access β -thalassemia is an inherited genetic disorder of hemoglobin synthesis (hemoglobinopathy), with an overall carrier rate of 1.5% in the world population. It is caused by mutations either in the β-globin gene or its promoter that result in reduced β-globin chain expression leading to an imbalance between α-and β-globin chains. Adult hemoglobin (HbA) primarily consists of 2 a chains and 2 b chains which coordinate a heme group. In β-thalassemia the reduction or absence of b-globin chains leads to the accumulation of unstable α-globin/heme complexes, called hemichromes, that easily precipitate and trigger reactive oxygen species (ROS) formation, thus contributing to ineffective erythropoiesis and anemia. 1 In β-thalassemia, expanded erythroid precursors produce elevated levels of the hormone erythroferrone (ERFE), which negatively controls the production of the iron-regulatory hormone hepcidin. Reduced hepcidin increases intestinal iron absorption and release from macrophages, resulting in progressive iron accumulation in tissues, a major complication in β-thalassemia, as well as in erythroid cells, thus aggravating ineffective erythropoiesis through increased hemichrome production.Anemia can range from mild to severe, based on which β-thalassemia patients are classified as nontransfusion-dependent (NTDT) or transfusion-dependent (TDT). Usually, patients with β-thalassemia major, due to almost complete absence of β-chains, have a greater and lifelong blood transfusion requirement along with iron chelation therapy, to limit complications associated with transfusional iron-overload. 2 So far, the only curative option for TDT patients is allogenic bone marrow transplantation, which is often limited by the availability of HLA-matched donors and in some cases associated with severe post-transplant complications. 3 Although novel therapeutic approaches including gene therapy with autologous hematopoietic stem cells modified ex vivo to restore β-globin expression, and the administration of the activin receptor ligand trap luspatercept have been recently approved for b-thalassemia patients, their applicability in subsets of selected patients and incomplete effectiveness limit their use. 4 These considerations highlight the need of therapeutic options to improve the current treatments for b-thalassemia.Recently, Di Modica and co-authors showed how the second transferrin receptor (TfR2) can be exploited for therapeutic purposes in TDT. 5 TfR2 is a transmembrane glycoprotein homologous to the classical transferrin receptor 1 (TfR1). While TfR1 is ubiquitously expressed and acts as main mechanism for cellular iron uptake through Tf-bound iron interaction, TfR2 is highly expressed in hepatocytes and rather involved in the regulation of hepcidin expression to modulate systemic iron levels. 5 Importantly, TfR2 was recently described as a sensor of circulating iron in erythroid cells, where it binds the erythropoietin (EPO) receptor (EPOR) and inhibits the activation of the EPO-EPOR signaling. Under condition ...

New partners for Luspatercept in β‐thalassemia

“…Thus, erythroid TfR2 deletion removes a ‘brake’ on erythropoiesis and promotes erythroid maturation by increasing EPO sensitivity 7 . The significant amelioration of ineffective erythropoiesis, anemia, and iron overload achieved by hematopoietic TfR2 deletion in preclinical murine models of β‐thalassemia recently highlighted TfR2 targeting as a viable therapeutic option for the disease 8,9 . Researchers led by Antonella Nai at the San Raffaele Institute in Milan evaluated whether enhanced EPO signaling could provide further advantage to RAP‐536 maturing action on erythroid precursors 3 …”

“…7 The significant amelioration of ineffective erythropoiesis, anemia, and iron overload achieved by hematopoietic TfR2 deletion in preclinical murine models of β-thalassemia recently highlighted TfR2 targeting as a viable therapeutic option for the disease. 8,9 Researchers led by Antonella Nai at the San Raffaele Institute in Milan evaluated whether enhanced EPO signaling could provide further advantage to RAP-536 maturing action on erythroid precursors. 3 In both studies, when tested in β-thalassemia animals, the combined approaches proved to be superior in the correction of anemia and improvement of hemoglobin and RBC parameters, compared with the single treatments.…”