Long-term control of erythropoietin secretion by doxycycline in mice transplanted with engineered primary myoblasts

Abstract

We investigated tetracycline regulation of gene expression in an experimental model relevant to gene therapy. Mouse primary myogenic cells were engineered for doxycycline-inducible and skeletal muscle-specific expression of the mouse erythropoietin (Epo) cDNA by using two retrovirus vectors. Gene expression increased 200 fold in response to both myogenic cell differentiation and doxycycline stimulation. After transplantation of transduced cells into mouse skeletal muscles, Epo secretion could be iteratively switched on and off over a five-month period, depending on the presence or the absence of doxycycline in the drinking water. We conclude that tetracycline regulation provides a suitable control system for adjusting the delivery of therapeutic proteins from engineered tissues over long periods of time.