The primary components of the human erythroid are erythroid marrow and circulating red blood cells (RBCs). Erythrocin abnormalities that cause anemia fall into three categories: erythroid hyperproliferation, inefficient erythropoiesis, and peripheral hemolysis. Erythropoietin-driven growth of early-stage erythroid precursors is coupled with apoptosis of late-stage precursors in ineffective erythropoiesis. This mechanism is predominantly responsible for anemia in hereditary illnesses such as -thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as several subtypes of myelodysplastic syndrome (MDS).
Because of the concomitant parenchymal iron loading induced by the release of erythroid hormones that limit hepcidin synthesis, hereditary anemias caused by inefficient erythropoiesis are also known as iron-loading anemias. Novel medicines were being explored to particularly target inefficient erythropoiesis. Iron limitation by increased hepcidin activity or suppression of ferroportin function has been proven to minimize inefficient erythropoiesis in -thalassemia murine models. Luspatercept is a TGF-ligand trap that suppresses SMAD2/3 signaling. The drug is currently licensed for the treatment of anemia in adult patients with -thalassemia who require frequent RBC transfusions based on preclinical and clinical trials. Luspatercept is also licensed to treat transfusion-dependent anemia in MDS patients with ring sideroblasts, the majority of whom had a somatic SF3B1 mutation.
While luspatercept’s long-term efficacy and safety in -thalassemia and MDS must be determined, identifying the molecular causes of poor erythropoiesis in other illnesses might lead to the development of additional beneficial drugs.