J Clin Invest. 2019 Dec 9;130(1):491-506. doi: 10.1172/JCI129382.
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.
β-地中海贫血是一种遗传性贫血，由β-球蛋白合成部分或完全缺失引起，导致无效的红细胞生成和红细胞寿命缩短。目前，β-地中海贫血患者尚无有效的口服药物来改善贫血。铁调节激素hepcidin 的水平过低，使铁蛋白（哺乳动物中唯一的细胞铁输出蛋白）过度吸收铁，导致器官铁过载和相关的病态。通过诱导 hepcidin 合成或使用 hepcidin 类似物治疗来纠正铁吸收和循环的不平衡，可以改善β-地中海贫血。然而，目前正在临床开发中的 hepcidin 调节或替代策略都需要进行肠外给药。我们通过筛选小分子化合物文库来寻找铁蛋白内化调节剂，从而确定了口服铁蛋白抑制剂。第一种临床阶段的口服铁蛋白抑制剂 VIT-2763 通过限制铁的可用性，改善了中间型β-地中海贫血 Hbbth3/+ 小鼠模型的贫血和铁代谢紊乱。VIT-2763 不仅改善了红细胞生成，还纠正了 Hbbth3/+ 小鼠脾脏中骨髓前体细胞的比例。VIT-2763 目前正在被开发为一种针对铁蛋白的口服药物，用于治疗β-地中海贫血。
