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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2793-2798
Improvement of erythropoiesis in  -thalassemic mice
by continuous erythropoietin delivery from muscle
Delphine Bohl,
Assumpció Bosch,
Ana Cardona,
Anna Salvetti, and
Jean Michel Heard
From the Laboratoire Rétrovirus et Transfert
Génétique and the Laboratoire de Technologie Cellulaire,
Institut Pasteur, Paris, France, and the Laboratoire de Thérapie
Génique, CHU-Hôtel-Dieu, Nantes, France.
 -Thalassemias are highly prevalent genetic disorders that can
cause severe hemolytic anemia. The main pathophysiologic feature of
-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 -minor globin in mice. In
contrast, long-term treatment of -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 -thalassemic mice, which represent a
suitable model for human -thalassemia intermedia. A 1-year follow-up
of 12 treated animals showed a stable correction of anemia associated
with improved RBC morphology, increased -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 -minor globin synthesis and a
stable improvement of erythropoiesis in the -thalassemic mouse model.
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