A Small Molecule Drug, Formoterol Fumarate, Potently Reverses Anemia

Abstract Anemia is a major societal health risk that greatly lowers quality of life in roughly a quarter of the world population1. However, current treatments are effective in only a subset of patients with hematological malignancies and disorders2,3. We have identified dynamic surface expression of β2-adrenoceptors in erythroid progenitors at various stages of differentiation. Here, we report that formoterol fumarate (FF), a highly selective β2-adrenoceptor agonist, promotes erythroid differentiation in the bone marrow and spleen to enhance hemoglobin and hematocrit levels in peripheral blood, thereby reversing anemia. FF treatment at very low doses via multiple routes of administration confers striking survival benefits in lethal hemolytic anemia. FF also boosts red blood cells in mouse models of myelodysplastic syndrome (MDS)/acute myeloid leukemia, chronic kidney disease (CKD), hemolytic stress-induced anemia, and in naïve mice at steady state. Furthermore, FF augments erythropoiesis in human stem cells derived from bone marrow aspirates of MDS patients. Mechanistically, FF promotes erythropoiesis partly via HIF-1α and associated hypoxia-responsive genes along with induction of mitochondrial biogenesis, thereby suggesting that the therapeutic relevance of FF may reflect its specific ability to induce coordinated HIF-1α and mitochondrial programs in addition to general β₂ activation. Importantly, we have developed a unique capsule formulation of FF that markedly reverses anemia when dosed orally in mice. Our study uncovers FF-driven stimulation of β2-adrenenoceptors as a new therapeutic strategy for treatment of anemia associated with MDS, CKD and hemolytic stress.