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

ß-thalassemia is a hereditary disorder caused by defective production of ß-globin chains of hemoglobin (Hb) that leads to an increased α/ß globins ratio with subsequent free α-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 ß (TGF-ß) 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-ß pathway, thus inhibiting the Smad2/3 cascade and alleviating anemia in patients with ß-thalassemia and myelodysplastic syndromes. In this review, we describe in extenso the TGF-ß pathway, as well as the molecular and biological basis of activin receptors ligand traps, focusing on their role in various ß-thalassemia experimental models. The most recent results from clinical trials on sotatercept and luspatercept will also be reviewed.