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

Abstract

Key Points• Investigation of the ironrestrictive effect of minihepcidin peptides in the treatment of b-thalassemia and polycythemia vera.In b-thalassemia and polycythemia vera (PV), disordered erythropoiesis triggers severe pathophysiological manifestations. b-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 th3/1 mice, which serve as a model of untransfused b-thalassemia, minihepcidin ameliorates ineffective erythropoiesis, anemia, and iron overload. In older mice with untransfused b-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 b-thalassemia and PV. (Blood. 2016;128(2):265-276)

Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of β-thalassemia intermedia and major

“…Compared to placebo-treated mice, flow cytometry studies revealed that animals receiving JAK2i exhibited a reduction in the number of erythroid nucleated cells in the spleen but not in the bone marrow (BM) ( Figure 1E and Online Supplementary Figure S1B). 12 This suggests that JAK2i might target preferentially rapidly proliferating erythroid progenitors in the spleen, as in extramedullary stress erythropoiesis. No differences were observed in serum HEPCIDIN levels (Online Supplementary figure 2A) or other iron parameters (Online Supplementary Figure S2B-F).…”

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

“…Thus, minihepcidins can be used as an adjunct to diseases with iron overload and ineffective erythropoiesis, such as β-thalassemia and polycythemia vera [172]. Other experiments are being conducted with the aim of increasing the utility of the minihepcidin molecule by improving the ease of its synthesis, reducing costs, and improving its bioavailability [173,174].…”

Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism

“…To this end, Ganz and his team have synthesized a series of mini-hepcidins; short peptides that maintain hepcidin action, are re-engineered to be stable, and could potentially be orally active [38,39] . In the global health context mini-hepcidin might be able to prevent the iron overload that occurs even in untransfused beta-thalassemia (due to the hepcidin-suppressing action of excess erythroferrone caused by the ineffective erythropoiesis that generates excess erythroblasts) [40] . Conversely, there is great interest in the possibility that hepcidin antagonists could be used to prevent or treat the anemia of chronic disease and anemias associated with treatments such as cancer chemotherapy [37] .…”