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 Hbb^th3/+ mouse model of β-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbb^th3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of β-thalassemia.

中文翻译：

---

口服铁转运蛋白抑制剂可改善β地中海贫血模型中无效的红细胞生成

β-地中海贫血是一种遗传性贫血，由β-珠蛋白合成的部分或全部丧失导致，导致无效的红细胞生成和寿命短的RBC。目前，尚无有效的口服药物治疗β地中海贫血患者的贫血。铁调节激素铁调素的含量过低会导致铁转运蛋白（哺乳动物中独特的细胞铁输出物）过度吸收铁，导致器官铁超载和相关的发病率。通过诱导铁调素合成或用铁调素模拟物治疗来纠正不平衡的铁吸收和循环利用，可改善β地中海贫血。然而，目前临床开发中的铁调素调节或替代策略均需要肠胃外给药。我们通过筛选小分子量化合物的铁转运蛋白内在调节剂库确定了口服铁转运蛋白抑制剂。通过临床第一阶段口服铁转运蛋白抑制剂VIT-2763限制铁的供应，改善了贫血和Hbb中铁稳态失调β-地中海贫血的^{th3 / +}小鼠模型。VIT-2763不仅改善了红细胞生成，还纠正了Hbb ^{th3 / +}小鼠脾脏中髓样前体的比例。目前正在开发VIT-2763作为靶向铁转运蛋白的口服药物，用于治疗β地中海贫血。