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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 3

VIT-2763 and hepcidin induce ferroportin internalization and ubiquitination.

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VIT-2763 and hepcidin induce ferroportin internalization and ubiquitinat...
(A) Representative images from fluorescence microscopy kinetic analysis of ferroportin internalization and degradation in MDCK cells constitutively expressing human ferroportin with a fluorescent HaloTag (green). Nuclei are depicted in red. Cells were incubated with either VIT-2763 (20 μM) or hepcidin (1 μM) for the indicated times. Scale bar: 25 μm. The full kinetic study shown in the figure was performed once. The experiment was repeated at individual time points: once at 6 hours, 3 times at 20 minutes and 1 hour, and more than 10 times at 3 hours and 18 hours with reproducible results. (B) Quantification of the ferroportin-associated membrane fluorescence in MDCK cells treated with serial dilutions of either hepcidin or VIT-2763 for 18 hours. n = 3 per concentration. Data are shown as mean ± SD for each concentration. (C) Kinetics of internalization of ferroportin, as depicted by decrease of membrane-associated ferroportin fluorescence in MDCK cells treated with either hepcidin (1 μM) or VIT-2763 (20 μM). n = 2 (1–6 hours); n = 3 (18 hours). Mean for each time point is shown. Data in B and C are presented as mean of the percentage of ferroportin membrane fluorescence relative to untreated cells. (D) Immunoprecipitation of J774 lysates for ubiquitination and degradation studies of ferroportin. J774 cells were treated with hepcidin (150 nM) or VIT-2763 (100 nM) for 10, 20, 40, 60, or 120 minutes before harvesting and IP with MTP1 anti-ferroportin antibody. Immunoprecipitates were blotted and stained with either ubiquitin-specific (upper blot) or ferroportin-specific (lower blot) antibody (F308). The full kinetic study shown in the figure was performed once. The experiment at time points 10 and 120 minutes was performed 5 times with reproducible results.
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