Control of erythropoietin secretion by doxycycline or mifepristone in mice bearing polymer-encapsulated engineered cells.
Cell encapsulation offers a safe and manufacturable method for the systemic delivery of therapeutic proteins from genetically engineered cells. However, control of dose delivery remains a major issue with regard to clinical application. We generated populations of immortalized murine NIH 3T3 fibroblasts that secrete mouse erythropoietin (Epo) in response to stimulation by doxycycline or mifepristone. Engineered cells were introduced into AN69 hollow 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, whereas animals not receiving the inducer drug had normal hematocrits. Epo secretion could be switched on and off, depending on the presence of doxycycline 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.
Laboratoire Rétrovirus et Transfert Génétique, CNRS URA 1157, Institut Pasteur, Paris, France.
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Serguera
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Bohl
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Rolland
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Prevost
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Heard
D016475:3T3 Cells; D000818:Animals; D015139:Blotting, Southern; D002214:Capsules; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology*; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006400:Hematocrit; D051379:Mice; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D012190:Retroviridae; D013997:Time Factors
D002214:Capsules; D004921:Erythropoietin; D015735:Mifepristone; D004318:Doxycycline