Activin Receptor-Ligand Trap for the Treatment of β-thalassemia: A Serendipitous Discovery

beta-thalassemia is a hereditary disorder caused by defective production of beta-globin chains of hemoglobin (Hb) that leads to an increased alpha/beta globins ratio with subsequent free alpha-globins. Alpha globin excess causes oxidative stress, red blood cells membrane damage, premature death of late-stage erythroid precursors, resulting in ineffective erythropoiesis. The transforming growth factor beta (TGF-beta) superfamily signaling acts on biological processes, such as cell quiescence, apoptosis, proliferation, differentiation, and migration, and plays an essential role in regulating the hematopoiesis. This pathway can lose its physiologic regulation in pathologic conditions, leading to anemia and ineffective erythropoiesis. Activin receptor-ligand trap molecules such as Sotatercept and Luspatercept downregulate the TGF-beta pathway, thus inhibiting the Smad2/3 cascade and alleviating anemia in patients with beta-thalassemia and myelodysplastic syndromes. In this review, we describe in extenso the TGF-beta pathway, as well as the molecular and biological basis of activin receptors ligand traps, focusing on their role in various beta-thalassemia experimental models. The most recent results from clinical trials on sotatercept and luspatercept will also be reviewed.