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

Mediterranean Journal of Hematology and Infectious Diseases
Valentina BrancaleoniIrene Motta

Abstract

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

Citations

Jun 8, 2021·HemaSphere·Maria Domenica CappelliniIrene Motta
Jul 2, 2021·Journal of Experimental Pharmacology·Clelia MadedduAntonio Macciò
Nov 13, 2021·Medicine·Tang-Her JaingChia-Chi Chiu

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Methods Mentioned

BETA
ubiquitination
RAP
MDS

Clinical Trials Mentioned

NCT01571635
NCT01749540
NCT02604433
NCT03342404
NCT01736683
NCT01749514
NCT02268383
NCT02631070

Software Mentioned

BEYOND

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