title: Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts.
abstract: The transplantation of polymer encapsulated myoblasts genetically engineered to secrete erythropoietin (Epo) may obviate the need for repeated parenteral administration of recombinant Epo as a treatment for chronic renal failure, cancer or AIDS-associated anemia. To explore this possibility, the human and mouse Epo cDNAs under the control of the housekeeping mouse PGK-1 promoter were transfected into mouse C2C12 myoblasts, which can be terminally differentiated upon exposure to low serum-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. Polyether-sulfone (PES) capsules loaded with approximately 200,000 transfected myoblasts from these pools were implanted on the dorsal flank of DBA/2J, C3H and C57BL/6 mice. With human Epo secreting capsules, only a transient increase in the hematocrit occurred in DBA/2J mice, whereas no significant response was detected in C3H or C57BL/6 mice. On the contrary, all mice implanted with capsules releasing mouse Epo increased their hematocrit over 85% as early as 7 days after implantation and sustained these levels for at least 80 days. All retrieved implants released Epo and contained well preserved myoblasts. Moreover most capsules were surrounded by a neovascularization. Mice transplanted with nonencapsulated C2C12 cells releasing mouse Epo showed only a transitory elevation of their hematocrit reflecting the poor engraftment of injected myoblasts. These results indicate that polymer encapsulation of genetically engineered myoblasts is a promising approach for the long-term delivery of bioactive molecules, allowing the resolution of the shortcomings of free myoblast transfer.
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000704:Analysis of Variance; D000740:Anemia / Q000209:etiology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood; D002214:Capsules; D002460:Cell Line; D004921:Erythropoietin / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006400:Hematocrit; D006801:Humans; D007273:Injections, Intramuscular; D007676:Kidney Failure, Chronic / Q000150:complications; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D009369:Neoplasms / Q000150:complications; D013997:Time Factors; D014162:Transfection