Isn't it ironic: better RBCs by blocking iron

In this issue of Blood, Nyffenegger et al(1) provide evidence that pharmacologic iron restriction improves disease parameters in the Townes mouse model of sickle cell disease (SCD). Prior studies in this model demonstrated that limiting iron absorption (by intestinal knockout of HIF 2 alpha(2) or by a low-iron diet(3)) led to hematologic improvements. To examine a pragmatic approach to iron restriction, the investigators used vamifeport, an orally administered inhibitor of the cellular iron exporter ferroportin.(4) Ferroportin is the only known means for cellular iron release, and functional loss is embryonic lethal.(5) However, manifestations of haploinsufficiency are seen primarily in cell types with high iron turnover (reticuloendothelial macrophages, enterocytes, and hepatocytes). Patients carrying an inactivating ferroportin allele have a generally mild condition (ferroportin disease type 4A), characterized by hepatic iron loading, relatively low serum iron, and marginally iron-restricted erythropoiesis. The latter consequence has been successfully advantaged in murine b-thalassemia(4) where ferroportin inhibition using vamifeport improved multiple hematologic parameters (see table).