RESUMEN
Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin-ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the Hfe C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in Hfe C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver Hamp in wild-type mice, which was absent in Hfe C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in Hfe C282Y mice, as well as markedly reducing liver Hamp expression in Hfe C282Y mice, suggesting distinct regulation of liver Hamp expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.
RESUMEN
ß-thalassemia is an inherited anemia characterized by ineffective erythropoiesis. Blood transfusions are required for survival in transfusion-dependent ß-thalassemia and are also occasionally needed in patients with non-transfusion-dependent ß-thalassemia. Patients with transfusion-dependent b-thalassemia often have elevated transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI) levels, which can lead to organ iron overload, oxidative stress, and vascular damage. Vamifeport is an oral ferroportin inhibitor that was previously shown to ameliorate anemia, ineffective erythropoiesis, and dysregulated iron homeostasis in the Hbbth3/+ mouse model of ß-thalassemia, under non-transfused conditions. Our study aimed to assess the effects of oral vamifeport on iron-related parameters (including plasma NTBI levels) and ineffective erythropoiesis following blood transfusions in Hbbth3/+ mice. A single dose of vamifeport prevented the transient transfusion-mediated NTBI increase in Hbbth3/+ mice. Compared with vehicle treatment, vamifeport significantly increased hemoglobin levels and red blood cell counts in transfused mice. Vamifeport treatment also significantly improved ineffective erythropoiesis in the spleens of Hbbth3/+ mice, with additive effects observed when treatment was combined with repeated transfusions. Vamifeport corrected leukocyte counts and significantly improved iron-related parameters (serum transferrin, TSAT and erythropoietin levels) versus vehicle treatment in Hbbth3/+ mice, irrespective of transfusion status. In summary, vamifeport prevented transfusion-mediated NTBI formation in Hbbth3/+ mice. When given alone or combined with blood transfusions, vamifeport also ameliorated anemia, ineffective erythropoiesis, and dysregulated iron homeostasis. Administering vamifeport together with repeated blood transfusions additively ameliorated anemia and ineffective erythropoiesis in this mouse model, providing preclinical proof-of-concept for the efficacy of combining vamifeport with blood transfusions in ß-thalassemia.
Asunto(s)
Sobrecarga de Hierro , Talasemia , Talasemia beta , Humanos , Ratones , Animales , Talasemia beta/tratamiento farmacológico , Eritropoyesis , Hierro/metabolismo , Transferrina/farmacología , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Transfusión SanguíneaRESUMEN
Sickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the ß-globin gene of hemoglobin that leads to synthesis of sickle hemoglobin (HbS) in red blood cells (RBCs). HbS polymerizes in hypoxic conditions, leading to intravascular hemolysis, release of free hemoglobin and heme, and increased adhesion of blood cells to the endothelial vasculature, which causes painful vaso-occlusion and organ damage. HbS polymerization kinetics are strongly dependent on the intracellular HbS concentration; a relatively small reduction in cellular HbS concentration may prevent HbS polymerization and its sequelae. We hypothesized that iron restriction via blocking ferroportin, the unique iron transporter in mammals, might reduce HbS concentration in RBCs, thereby decreasing hemolysis, improving blood flow, and preventing vaso-occlusive events. Indeed, vamifeport (also known as VIT-2763), a clinical-stage oral ferroportin inhibitor, reduced hemolysis markers in the Townes model of SCD. The RBC indices of vamifeport-treated male and female Townes mice exhibited changes attributable to iron-restricted erythropoiesis: decreased corpuscular hemoglobin concentration mean and mean corpuscular volume, as well as increased hypochromic and microcytic RBC fractions. Furthermore, vamifeport reduced plasma soluble VCAM-1 concentrations, which suggests lowered vascular inflammation. Accordingly, intravital video microscopy of fluorescently labeled blood cells in the microvasculature of Townes mice treated with vamifeport revealed diminished adhesion to the endothelium and improved hemodynamics. These preclinical data provide a strong proof-of-concept for vamifeport in the Townes model of SCD and support further development of this compound as a potential novel therapy in SCD.
Asunto(s)
Anemia de Células Falciformes , Hemólisis , Anemia de Células Falciformes/complicaciones , Animales , Proteínas de Transporte de Catión , Modelos Animales de Enfermedad , Femenino , Hemodinámica , Hemoglobina Falciforme/genética , Hemoglobina Falciforme/metabolismo , Hemoglobinas/metabolismo , Hierro/uso terapéutico , Masculino , Mamíferos/metabolismo , RatonesRESUMEN
Intravenously administered iron-carbohydrate preparations are a structurally heterogenous class of nanomedicines. Iron biodistribution to target tissues is greatly affected by the physicochemical characteristics of these nanoparticles. Some regulatory agencies have recommended performing studies in animal models for biodistribution characterization and bioequivalence evaluation. In the present work, a systematic comparison of iron exposure, tissue biodistribution and pharmacodynamics of four intravenous iron-carbohydrates in anemic CD rats was conducted. A pilot study was performed to establish the anemic rat model, followed by a control study to evaluate the pharmacokinetics (serum iron, biodistribution) and pharmacodynamics (hematological parameters) in healthy and anemic controls and anemic rats receiving ferric carboxymaltose (FCM). The same parameters were then evaluated in a comparative study in anemic rats receiving FCM, iron sucrose (IS), iron isomaltoside 1000 (IIM), and iron dextran (ID). Despite similar serum iron profiles observed across the investigated nanomedicines, tissue iron biodistribution varied markedly between the individual intravenous iron-carbohydrate complexes. Tissue iron repletion differences were also confirmed by histopathology. These results suggest that employing serum iron profiles as a surrogate for tissue biodistribution may be erroneous. The variability observed in tissue biodistribution may indicate different pharmacodynamic profiles and warrants further study.
Asunto(s)
Hierro , Nanomedicina , Animales , Carbohidratos , Compuestos Férricos/química , Maltosa , Proyectos Piloto , Ratas , Distribución TisularRESUMEN
In ß-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of ß-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of ß-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in ß-thalassemia.
Asunto(s)
Bencimidazoles/farmacología , Eritropoyesis/efectos de los fármacos , Oxazoles/farmacología , Piridinas/farmacología , Talasemia beta/tratamiento farmacológico , Administración Oral , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/uso terapéutico , Proteínas de Transporte de Catión/antagonistas & inhibidores , Células Cultivadas , Deferasirox/administración & dosificación , Deferasirox/farmacología , Deferasirox/uso terapéutico , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Hierro/sangre , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Oxazoles/administración & dosificación , Oxazoles/efectos adversos , Oxazoles/uso terapéutico , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Transferrina/metabolismoRESUMEN
ß-Thalassemia is a genetic anemia caused by partial or complete loss of ß-globin synthesis, leading to ineffective erythropoiesis and RBCs with a short life span. Currently, there is no efficacious oral medication modifying anemia for patients with ß-thalassemia. The inappropriately low levels of the iron regulatory hormone hepcidin enable excessive iron absorption by ferroportin, the unique cellular iron exporter in mammals, leading to organ iron overload and associated morbidities. Correction of unbalanced iron absorption and recycling by induction of hepcidin synthesis or treatment with hepcidin mimetics ameliorates ß-thalassemia. However, hepcidin modulation or replacement strategies currently in clinical development all require parenteral drug administration. We identified oral ferroportin inhibitors by screening a library of small molecular weight compounds for modulators of ferroportin internalization. Restricting iron availability by VIT-2763, the first clinical stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of ß-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbbth3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of ß-thalassemia.