CONTINUOUS DELIVERY OF HUMAN AND MOUSE ERYTHROPOIETIN IN MICE BY GENETICALLY-ENGINEERED POLYMER ENCAPSULATED MYOBLASTS

The transplantation of polymer encapsulated myoblasts genetically engi neered to secrete erythropoietin (Epo) may obviate the need for repeat ed parenteral administration of recombinant Epo as a treatment for chr onic renal failure, cancer or AIDS-associated anemia. To explore this possibility, the human and mouse Epo cDNAs under the control of the ho usekeeping mouse PGK-I promoter were transfected into mouse C2C12 myob lasts, which can be terminally differentiated upon exposure to low ser um-containing media. Pools releasing 150 IU human Epo per 10(6) cells per day and 390 IU mouse Epo per 10(6) cells per day were selected. Po lyether-sulfone (PES) capsules loaded with approximately 200 000 trans fected myoblasts from these pools were implanted on the dorsal flank o f DBA/2J, C3H and C57BL/6 mice. With human Epo secreting capsules, onl y a transient increase in the hematocrit occurred in DBA/2J mice, wher eas no significant response was detected in C3H or C57BL/6 mice. On th e contrary, all mice implanted with capsules releasing mouse Epo incre ased their hematocrit over 85% as early as 7 days after implantation a nd sustained these levels for at least 80 days. All retrieved implants released Epo and contained well preserved myoblasts. Moreover most ca psules were surrounded by a neovascularization. Mice transplanted with nonencapsulated C2C12 cells releasing mouse Epo showed only a transit ory elevation of their hematocrit reflecting the poor engraftment of i njected myoblasts. These results indicate that polymer encapsulation o f genetically engineered myoblasts is a promising approach for the lon g-term delivery of bioactive molecules, allowing the resolution of the shortcomings of free myoblast transfer.