Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

• Published in: Blood Vol. 120; no. 18; pp. 3829 - 3836
• Main Authors: Ramos, Emilio, Ruchala, Piotr, Goodnough, Julia B., Kautz, Léon, Preza, Gloria C., Nemeth, Elizabeta, Ganz, Tomas
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Anemia, Iron-Deficiency - chemically induced; Animals; Antimicrobial Cationic Peptides - agonists; Antimicrobial Cationic Peptides - deficiency; Antimicrobial Cationic Peptides - pharmacology; Biological and medical sciences; Chromatography, High Pressure Liquid; Disease Models, Animal; Hematologic and hematopoietic diseases; Hemochromatosis - prevention & control; Hepcidins; Iron Overload - prevention & control; Male; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Mice; Mice, Inbred C57BL; Mice, Knockout; Other metabolic disorders; Red Cells, Iron, and Erythropoiesis; Iron overload; Animal model; Hemochromatosis; Hematology; Rodentia; Metabolic diseases; Iron; Enzymopathy; Prevention; Vertebrata; Mammalia; Mouse; Hepcidin
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-07-440743

The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation.