Concurrent Treatment with Minhepcidin and Deferiprone Improves Anemia and Enhances Reduction of Spleen Iron in a Mouse Model of Non-Transfusion Dependent Thalassemia

• Published in: Blood 2014-12, Vol.124 (21), p.748-748
• Main Authors: Casu, Carla, Oikonomidau, Rea, Shah, Yatrik, Nemeth, Elizabeta, Ganz, Tomas, MacDonald, Brian, Rivella, Stefano
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.748.748

Individuals affected by non-transfusion-dependent thalassemia (NTDT) develop severe ineffective erythropoiesis that causes a number of serious clinical morbidities, such as chronic anemia, splenomegaly and systemic iron overload requiring chelation therapy. In NTDT, low hepcidin levels caused by ineffective erythropoiesis result in increased iron absorption which may in turn exacerbate erythroid cell damage, apoptosis and ineffective erythropoiesis. Minihepcidins (MH) are short peptide mimetics that reproduce the iron restrictive effects of hepcidin. Using a mouse model of NTDT (Hbbth3/+), we previously showed that MH-induced iron restriction significantly reduced erythroid cell damage, leading to reduced ineffective erythropoiesis and improved anemia. Accumulation of tissue iron was significantly diminished in MH treated animals. In clinical settings, use of MH for the treatment of NTDT would likely be concomitant with oral chelation therapy. Therefore we conducted studies in the (Hbbth3/+) mouse to evaluate whether the concurrent use of the oral iron chelator deferiprone (DFP) and MH would alter a) the hematological benefit of MH or b) the tissue iron reduction benefit of DFP. MH may improve the efficacy of DFP by reducing dietary iron absorption, thus increasing net reduction in tissue iron. Studies were performed in six week old mice using MH M004, which reduces cell surface expression of ferroportin with an EC50of 9.7 nM and causes >80% reduction in serum iron at a dose of 7.5 mg/kg in the rat. M004 (2.65 mg/kg) or vehicle control was administered twice weekly by subcutaneous injection for six weeks. Half of the mice in each group had free access to water containing DFP (1.25 mg/mL). Treatment with MH alone produced a profile of hematological changes resulting in a significant increase in circulating hemoglobin of 1.6 g/dL. Flow cytometry studies of bone marrow erythroid populations from MH-treated animals demonstrated an increase in the relative proportion of mature erythroid cells, reduced apoptosis and reduced levels of ROS. Parameters of erythrocyte damage (red cell distribution width, red cell morphology, red cell survival time) were improved and an increase in peripheral red cell number was observed. Reticulocyte count and spleen size were both reduced, reflecting improved erythropoietic efficiency. In separate studies in Hbbth3/+ mice that also expressed a hypoxia induced luciferase-reporter gene, treatment with MH resulted in reduction of tiss