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Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia
Vania Manolova, … , Hanna Sundstrom, Franz Dürrenberger
Vania Manolova, … , Hanna Sundstrom, Franz Dürrenberger
Published October 22, 2019
Citation Information: J Clin Invest. 2020;130(1):491-506. https://doi.org/10.1172/JCI129382.
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Research Article Hematology

Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia

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Abstract

β-Thalassemia is a genetic anemia caused by partial or complete loss of β-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 β-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 β-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 β-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 β-thalassemia.

Authors

Vania Manolova, Naja Nyffenegger, Anna Flace, Patrick Altermatt, Ahmet Varol, Cédric Doucerain, Hanna Sundstrom, Franz Dürrenberger

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Figure 11

VIT-2763 reduced hypoxia response in RBCs, excessive serum EPO, and Erfe expression in spleens of Hbbth3/+ mice without effect on liver Hamp.

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VIT-2763 reduced hypoxia response in RBCs, excessive serum EPO, and Erfe...
(A) Percentage of hypoxic RBCs (left, dot plots) and MFI of the hypoxia probe (right, Hypoxia probe+ RBCs) in peripheral blood of Hbbth3/+ mice or WT mice, as detected by flow cytometry analysis. n = 10–13 mice per group. Representative dot plots showing 1 out of 2 independent experiments. (B) Serum EPO was measured by ELISA. n = 10–13. (C) Spleen Erfe (Fam132) (n = 4–13 mice per group) and liver Hamp (D) gene expression were measured by qPCR (n = 10-11 mice). (A–D) Individual values and mean ± SD are shown. Statistical analysis was performed by comparing all treatment groups to the Hbbth3/+ vehicle group using 1-way ANOVA with Dunnett’s multiple comparison test. *P < 0.05; ***P < 0.001.
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