title: Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia.
abstract: In β-thalassemia, unequal production of α- and β-globin chains in erythroid precursors causes apoptosis and inhibition of late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Here we used a murine model of β-thalassemia intermedia (Hbb(th1/th1) mice) to investigate effects of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 signaling. In Hbb(th1/th1) mice, treatment with RAP-536 reduced overactivation of Smad2/3 in splenic erythroid precursors. In addition, treatment of Hbb(th1/th1) mice with RAP-536 reduced α-globin aggregates in peripheral red cells, decreased the elevated reactive oxygen species present in erythroid precursors and peripheral red cells, and alleviated anemia by promoting differentiation of late-stage erythroid precursors and reducing hemolysis. Notably, RAP-536 treatment mitigated disease complications of IE, including iron overload, splenomegaly, and bone pathology, while reducing erythropoietin levels, improving erythrocyte morphology, and extending erythrocyte life span. These results implicate signaling by the transforming growth factor-β superfamily in late-stage erythropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for thalassemia syndrome and other red cell disorders characterized by IE.
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Rajasekhar N V S
authors.initials: RN
authors.lastname: Suragani
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Cawley
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Li
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Samantha
authors.initials: S
authors.lastname: Wallner
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Alexander
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Mulivor
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, and.
authors.forename: Sara
authors.initials: S
authors.lastname: Gardenghi
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, and Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Asya V
authors.initials: AV
authors.lastname: Grinberg
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Pearsall
authors.affiliation: Acceleron Pharma, Cambridge, MA; and.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000740:Anemia / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D017086:beta-Thalassemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics; D006461:Hemolysis / Q000187:drug effects / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: C425584:activin receptor type II-B; D030301:Activin Receptors, Type II; D055544:beta-Globins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; C000621232:luspatercept