Improvement of erythropoiesis in β-thalassemic mice by continuous erythropoietin delivery from muscle

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Abstract
β-Thalassemias are highly prevalent genetic disorders that can cause severe hemolytic anemia. The main pathophysiologic feature of β-thalassemia is the accumulation of unpaired -globin chains in erythrocyte precursors and red blood cells (RBCs). This accumulation alters cell membrane function and results in early cell destruction and ineffective erythropoiesis. Correction of globin chain imbalance through the induction of fetal hemoglobin (HbF) synthesis is a tentative therapeutic approach for this class of diseases. In short-term in vitro or in vivo assays, recombinant human erythropoietin increases the frequency of erythroid precursors programmed to HbF in humans and to β-minor globin in mice. In contrast, long-term treatment of β-thalassemic patients did not induce HbF significantly. We took advantage of highly efficient adeno-associated virus–mediated (AAV-mediated) gene transfer into mouse muscle to induce a robust and sustained secretion of mouse erythropoietin in β-thalassemic mice, which represent a suitable model for human β-thalassemia intermedia. A 1-year follow-up of 12 treated animals showed a stable correction of anemia associated with improved RBC morphology, increased β-minor globin synthesis, and decreased amounts of -globin chains bound to erythrocyte membranes. More effective erythropoiesis probably accounted for a reduction of erythroid cell proliferation, as shown by decreased proportions of circulating reticulocytes and by reduced iron 59 (59Fe) incorporation into erythroid tissues. This study indicates that the continuous delivery of high amounts of autologous erythropoietin induced a sustained stimulation of β-minor globin synthesis and a stable improvement of erythropoiesis in the β-thalassemic mouse model.