Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts
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.
Keywords: Acquired Immunodeficiency Syndrome/complications ; Analysis of Variance ; Anemia/etiology/ therapy ; Animals ; Antibodies ; Monoclonal/blood ; Capsules ; Cell Line ; Erythropoietin/ administration & dosage/genetics/ secretion ; Female ; Gene Therapy/ methods ; Genetic Engineering/methods ; Genetic Vectors ; Hematocrit ; Humans ; Injections ; Intramuscular ; Kidney Failure ; Chronic/complications ; Mice ; Mice ; Inbred C3H ; Mice ; Inbred C57BL ; Mice ; Inbred DBA ; Muscle ; Skeletal/cytology/ secretion/ transplantation ; Neoplasms/complications ; Time Factors ; Transfection
Division of Surgical Research, Centre Hospitalier Universitaire Vaudois, Lausanne University Medical School, Switzerland.
Record created on 2007-03-09, modified on 2016-08-08