Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia

Suragani, Rajasekhar Nvs; Cawley, Sharon M; Li, Robert; Wallner, Samantha; Alexander, Mark J.; Mulivor, Aaron W.; Gardenghi, Sara; Rivella, Stefano; Grinberg, Asya V.; Pearsall, R. Scott; Kumar, Ravindra

doi:10.1182/blood-2013-06-511238

Cited by 131 publications

(170 citation statements)

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“…141 The observation triggered further investigation into this, and another trap ligand targeting ActRIIB (ACE-536), in mouse models of myelodysplastic syndromes (MDS) as well as b-thalassemia, showed a significant improvement of the anemia. [142][143][144] In both these disorders it has been suggested that the mechanism of action of these drugs is mediated by targeting Gdf11, which in turn decreases Smad2/3 activation in erythroid progenitors, and ultimately improves erythroid maturation and RBC production. [142][143][144] In addition, in Hbb th1/th1 mice, it has been shown that oxidative stress, through the Gdf11 ligand (Figure 3), also decreases apoptosis through overactivation of the Fas-Fas ligand pathway.…”

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“…[142][143][144] In both these disorders it has been suggested that the mechanism of action of these drugs is mediated by targeting Gdf11, which in turn decreases Smad2/3 activation in erythroid progenitors, and ultimately improves erythroid maturation and RBC production. [142][143][144] In addition, in Hbb th1/th1 mice, it has been shown that oxidative stress, through the Gdf11 ligand (Figure 3), also decreases apoptosis through overactivation of the Fas-Fas ligand pathway. 126,127 As mentioned previously, both decreased apoptotic rate and maturation of early erythroid precursors leads to exacerbation of IE, splenomegaly, and increased iron absorption.…”

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-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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b-thalassemias are monogenic disorders characterized by defective synthesis of the b-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the b-globin gene or its regulatory elements have been associated with b-thalassemias. Due to the complexity of the regulation of the b-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of b-globin and abnormal erythropoiesis, as well as current and novel therapies. ABSTRACTThe complex phenotype of b-thalassemias b-thalassemias are monogenic disorders characterized by reduced or no synthesis of the b-globin chain, one of the major components of adult hemoglobin (HbA). Several hundred mutations in the b-globin gene or regulatory elements have been associated with b-thalassemias.

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-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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“…Complexes containing ActRIIA, ActRIIB, or Tgfβ type II receptor regulate gene expression primarily by activating the Smad2/3 subfamily of intracellular effectors. 37,38 Overactivation of the Smad2/3 complex has been associated with an abnormal ratio between immature and mature erythroblasts, leading to expansion of the erythron and abortive erythroid precursor maturation. 37,38 Both RAP-011 and RAP-536 inhibit Smad2/3 signaling in erythroid cells.…”

Section: Targeting Ineffective Erythropoiesis: Experimental Observatimentioning

confidence: 99%

“…37,38 Overactivation of the Smad2/3 complex has been associated with an abnormal ratio between immature and mature erythroblasts, leading to expansion of the erythron and abortive erythroid precursor maturation. 37,38 Both RAP-011 and RAP-536 inhibit Smad2/3 signaling in erythroid cells. In particular, RAP-011 acts by targeting Gdf11, which is up-regulated in thalassemic erythroid cells and is associated with increased Smad2/3 activation.…”

Section: Targeting Ineffective Erythropoiesis: Experimental Observatimentioning

confidence: 99%

Iron age: novel targets for iron overload

Casu¹,

Rivella

2014

Hematology

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Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

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“…It has been recently demonstrated that a mouse version of both drugs, termed RAP-011 and RAP-536, is able to induce differentiation of erythroid cells, improve ineffective erythropoiesis, correct anemia, and limit iron overload in a mouse model of β-thalassemia intermedia. 12,13 Both drugs act through inhibition of GDF11, a newly identified regulator of erythropoiesis that will contribute significantly to the understanding of the fine regulation of erythropoiesis and iron metabolism, and to the development of new drugs. So far, two phase II clinical trials have provided proof of the importance of ActR ligand trap molecules in the use of sotatercept in adults with β-thalassemia (clinicaltrials.gov identifier: 01571635) and in transfusion-dependent DBA patients (clinicaltrials.gov identifier: 01464164).…”

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