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Blood. 2016 Jul 14;128(2):265-76. doi: 10.1182/blood-2015-10-676742. Epub 2016 May 6.

Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera.

Author information

1
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; Division of Hematology-Oncology, Department of Pediatrics, Weill Cornell Medical College, New York, NY;
2
Erythropoiesis Laboratory, and.
3
Laboratory Data Analytic Services, New York Blood Center, New York, NY;
4
Department of Pediatrics, and.
5
Department of Pediatrics, and Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO;
6
Department of Molecular and Integrative Physiology, and Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
7
Department of Medicine, and.
8
Department of Medicine, and Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA;
9
Merganser Biotech Inc., King of Prussia, PA;
10
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; Division of Hematology-Oncology, Department of Pediatrics, Weill Cornell Medical College, New York, NY; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY; and Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA.

Abstract

In β-thalassemia and polycythemia vera (PV), disordered erythropoiesis triggers severe pathophysiological manifestations. β-Thalassemia is characterized by ineffective erythropoiesis, reduced production of erythrocytes, anemia, and iron overload and PV by erythrocytosis and thrombosis. Minihepcidins are hepcidin agonists that have been previously shown to prevent iron overload in murine models of hemochromatosis and induce iron-restricted erythropoiesis at higher doses. Here, we show that in young Hbb(th3/+) mice, which serve as a model of untransfused β-thalassemia, minihepcidin ameliorates ineffective erythropoiesis, anemia, and iron overload. In older mice with untransfused β-thalassemia, minihepcidin improves erythropoiesis and does not alter the beneficial effect of the iron chelator deferiprone on iron overload. In PV mice that express the orthologous JAK2 mutation causing human PV, administration of minihepcidin significantly reduces splenomegaly and normalizes hematocrit levels. These studies indicate that drug-like minihepcidins have a potential as future therapeutics for untransfused β-thalassemia and PV.

PMID:
27154187
PMCID:
PMC4946204
DOI:
10.1182/blood-2015-10-676742
[Indexed for MEDLINE]
Free PMC Article

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