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

beta-Thalassemias are highly prevalent genetic disorders that can cause sev ere hemolytic anemia. The main pathophysiologic feature of beta-thalassemia is the accumulation of unpaired cu-globin chains in erythrocyte precursors and red blood cells (RBCs), This accumulation alters cell membrane functio n and results in early cell destruction and ineffective erythropoiesis, Cor rection of globin chain imbalance through the induction of fetal hemoglobin (HbF) synthesis is a tentative therapeutic approach for this class of dise ases. In short-term in vitro or in vivo assays, recombinant human erythropo ietin increases the frequency of erythroid precursors programmed to HbF in humans and to beta-minor globin in mice, In contrast, long-term treatment o f beta-thalassemic patients did not induce HbF significantly, We took advan tage of highly efficient adeno-associated virus-mediated (AAV-mediated) gen e transfer into mouse muscle to induce a robust and sustained secretion of mouse erythropoietin in beta-thalassemic mice, which represent a suitable m odel for human beta-thalassemia intermedia. A 1-year follow-up of 12 treate d animals showed a stable correction of anemia associated with improved RBC morphology, increased beta-minor globin synthesis, and decreased amounts o f alpha-globin chains bound to erythrocyte membranes, More effective erythr opoiesis probably accounted for a reduction of erythroid cell proliferation , as shown by decreased proportions of circulating reticulocytes and by red uced iron 59 (Fe-59) incorporation into erythroid tissues. This study indic ates that the continuous delivery of high amounts of autologous erythropoie tin induced a sustained stimulation of beta-minor globin synthesis and a st able improvement of erythropoiesis in the beta-thalassemic mouse model, (Bl ood, 2000;95:2793-2798) (C) 2000 by The American Society of Hematology.