Sickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the β-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.

中文翻译：

---

口服铁转运蛋白抑制剂 vamifeport 可改善镰状细胞病小鼠模型的血液动力学。

镰状细胞病 (SCD) 是一种遗传性溶血性贫血，由血红蛋白 β-珠蛋白基因的单点突变引起，导致红细胞 (RBC) 中合成镰状血红蛋白 (HbS)。HbS 在缺氧条件下聚合，导致血管内溶血，释放游离血红蛋白和血红素，增加血细胞对内皮血管的粘附，从而导致疼痛性血管闭塞和器官损伤。HbS 聚合动力学强烈依赖于细胞内 HbS 浓度；细胞 HbS 浓度相对较小的降低可能会阻止 HbS 聚合及其后遗症。我们假设通过阻断哺乳动物中独特的铁转运蛋白铁转运蛋白来限制铁可能会降低红细胞中的 HbS 浓度，从而减少溶血，改善血流，并预防血管闭塞事件。事实上，vamifeport（也称为 VIT-2763）是一种临床阶段的口服铁转运蛋白抑制剂，可减少 SCD Townes 模型中的溶血标志物。vamifeport 治疗的雄性和雌性 Townes 小鼠的 RBC 指数表现出可归因于铁限制性红细胞生成的变化：红细胞血红蛋白浓度平均值和平均红细胞体积降低，以及低色素和小细胞 RBC 分数增加。此外，vamifeport 降低了血浆可溶性 VCAM-1 浓度，这表明血管炎症降低了。因此，用 vamifeport 治疗的 Townes 小鼠微血管系统中荧光标记血细胞的活体视频显微镜显示，与内皮细胞的粘附减少，血液动力学得到改善。