An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia

Nat Med. 2014 Apr;20(4):398-407. doi: 10.1038/nm.3468. Epub 2014 Mar 23.


The pathophysiology of ineffective erythropoiesis in β-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of β-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in β-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / metabolism*
  • Animals
  • Apoptosis / physiology
  • Autocrine Communication / physiology
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation
  • Disease Models, Animal
  • Erythroblasts / metabolism*
  • Erythropoiesis / drug effects*
  • Fas Ligand Protein
  • Gene Amplification / physiology
  • Growth Differentiation Factors / antagonists & inhibitors*
  • Growth Differentiation Factors / metabolism
  • Hematinics / pharmacology*
  • Ligands
  • Mice
  • Oxidative Stress / physiology
  • Reactive Oxygen Species
  • Recombinant Fusion Proteins / pharmacology*
  • Signal Transduction
  • beta-Thalassemia / metabolism*
  • fas Receptor


  • ACE-011
  • Bone Morphogenetic Proteins
  • Fas Ligand Protein
  • GDF11 protein, human
  • Gdf11 protein, mouse
  • Growth Differentiation Factors
  • Hematinics
  • Ligands
  • Reactive Oxygen Species
  • Recombinant Fusion Proteins
  • fas Receptor
  • Activin Receptors, Type II
  • activin receptor type II-A