Open AccessACTIVIN RECEPTOR LIGAND FOR THR TREATMENT OF BETA-THALASSEMIA: a SERENDIPITOUS DISCOVERY
Author(s) -
Valentina Brancaleoni,
Isabella Nava,
Paola Delbini,
Lorena Duca,
Irene Motta
Publication year - 2020
Publication title -
mediterranean journal of hematology and infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.682
H-Index - 31
ISSN - 2035-3006
DOI - 10.4084/mjhid.2020.075
Subject(s) - ineffective erythropoiesis , erythropoiesis , thalassemia , medicine , activin receptor , receptor , globin , cancer research , anemia , downregulation and upregulation , apoptosis , microbiology and biotechnology , immunology , hemoglobin , biology , genetics , gene
b-thalassemia is a hereditary disorder caused by defective production of b-globin chains of hemoglobin (Hb) that leads to an increased a/b globins ratio with subsequent free a-globins. Alpha globin excess causes oxidative stress, RBCs membrane damage, premature death of late-stage erythroid precursors, resulting in ineffective erythropoiesis.
The transforming growth factor b (TGF-b) superfamily signaling acts on biological processes, such as cell quiescence, apoptosis, proliferation, differentiation, and migration, and also plays an important role in the regulation of 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-b pathway by inhibiting the Smad2/3 cascade, thus alleviating anemia in patients with b-thalassemia and myelodysplastic syndromes.
In this review, we describe in extenso the TGF-b pathway, as well as the molecular and biological basis of activin receptors ligand traps, focusing on their role in various b-thalassemia experimental models. The most recent results from clinical trials on sotatercept and luspatercept will also be reviewed.