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Red Cell Biology & its Disorders
Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult β-thalassemia major
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1835-1844
Carla Casu,1* Roberta Chessa,1* Alison Liu,1 Ritama Gupta,1 Hal Drakesmith,2 Robert Fleming,3 Yelena Z. Ginzburg,4 Brian MacDonald5 and Stefano Rivella1
1Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA; 2MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK; 3Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO, USA; 4Division of Hematology and Medical Oncology, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA and 5Merganser Biotech Inc. King of Prussia, PA, USA
*CC and RC contributed equally as co-first authors.
ABSTRACT
Minihepcidins are hepcidin agonists that have been previously shown to reverse iron overload and improve erythropoiesis in mice affected by non-transfusion-dependent thalassemia. Given the extreme anemia that occurred with the previous model of transfusion- dependent thalassemia, that model was inadequate for investigating whether minihepcidins can improve red blood cell quality, lifespan and inef- fective erythropoiesis. To overcome this limitation, we generated a new murine model of transfusion-dependent thalassemia with severe anemia and splenomegaly, but sufficient red cells and hemoglobin production to test the effect of minihepcidins. Furthermore, this new model demonstrates cardiac iron overload for the first time. In the absence of transfusions, minihepcidins improved red blood cell morphology and lifespan as well as ineffective ery- thropoiesis. Administration of a minihepcidin in combination with chronic red blood cell transfusion further improved the ineffective erythropoiesis and splenomegaly and reversed cardiac iron overload. These studies indicate that drugs such as minihepcidins have therapeutic potential for patients with transfusion-dependent thalassemia.
Introduction
Non-transfusion and transfusion-dependent thalassemia (NTDT and TDT, respectively) are characterized by imbalanced synthesis of α- and β-globin chains, leading to the formation of unstable α-globin chain/heme aggregates (hemichromes) in erythroid cells. Hemichromes impair the differentiation and sur- vival of erythroid progenitors as well as the lifespan of enucleated red blood cells (RBC).1-6
Both NTDT and TDT patients suffer from iron overload and require chronic iron chelation therapy to prevent major complications, such as liver and heart failure.5-9 The mechanism leading to iron accumulation in organs is different in NTDT vs. TDT.5,6,10,11 In NTDT, iron overload is likely mediated by a variety of factors, includ- ing increased erythropoiesis, hypoxia and the contribution of factors such as ery- throferrone, which suppresses hepcidin synthesis in the liver.12-16 Because hepcidin functionally inhibits iron egress from cells by binding and internalizing the iron transporter ferroportin in enterocytes, iron absorption is increased under condi- tions of reduced hepcidin synthesis.3,16-18 Additionally, in hypoxic conditions, syn- thesis of molecules responsible for mediating iron absorption (including ferro- portin) are increased in the duodenum, further contributing to the iron overload in NTDT.4,19,20 In contrast to NTDT patients, TDT patients require chronic RBC trans- fusion for survival.9,18,21 Because transfused RBC ultimately undergo senescence and require removal by splenic and liver macrophages and because there is no physio-
Correspondence:
STEFANO RIVELLA
rivellas@email.chop.edu
Received: November 19, 2018. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2018.212589
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/7/1835
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