Mechanisms leading to sustained reversion of β-thalassemia in mice by doxycycline-controlled epo delivery from muscles

Abstract

Erythropoiesis has been considered as a potential treatment for β-thalassemia. Although Epo secretion from genetically engineered muscles allowed long-term correction of the disease in the mouse, repeated injections of rHuEpo were disappointing in human patients. Whether different mechanisms operate in humans and mice or whether Epo exhibits different biological activity depending on the administration route is currently unknown. We provide evidence that mechanisms recruited over a 36-week follow-up in β-thalassemic mice were similar to those acting during stress-induced erythropoiesis in humans. β-Thalassemic mice were rendered steadily normocythemic by the intramuscular injection of a tetracycline-inducible AAV vector encoding mouse Epo. Doxycycline dosage was adapted to hematocrit. Circulating red blood cells essentially synthesized β-minor globin, the mouse equivalent to human γ-globin. Quantification of erythroid progenitors indicated a steady-state expansion of erythroid burst-forming units programmed for β-minor globin synthesis and a hastening of their maturation to hemoglobin-synthesizing cells. We discuss hypotheses that could account for the failure to recruit this mechanism over the long term in β-thalassemic patients and raise the possibility of Epo gene therapy trials to treat β-thalassemia.