Control of erythropoietin secretion by doxycycline or mifepristone in micebearing polymer-encapsulated engineered cells

Cell encapsulation offers a safe and manufacturable method for the systemic delivery of therapeutic proteins from genetically engineered cells. Howeve r, control of dose delivery remains a major issue with regard to clinical a pplication. We generated populations of immortalized murine NIH 3T3 fibrobl asts that secrete mouse erythropoietin (Epo) in response to stimulation by doxycycline or mifepristone, Engineered cells were introduced into AN69 hol low fibers, which were implanted in the peritoneal cavity or recipient mice . Animals receiving doxycycline or mifepristone showed stable polyhemia and increased serum Epo concentrations over a 6-month observation period, wher eas animals not receiving the inducer drug had normal hematocrits, Epo secr etion could be switched on and off, depending on the presence of doxycyclin e in the drinking water. In contrast, polyhemia was hardly reversible after subcutaneous injections of mifepristone, These data show that a permanent and regulated systemic delivery of a therapeutic protein can be obtained by the in vivo implantation of engineered allogeneic cells immunoprotected in membrane polymers.