Delivery of recombinant product from subcutaneous implants of encapsulated recombinant cells in canines.
Delivering recombinant therapeutic proteins from a universal microencapsulated cell line is an alternate method for gene therapy. It has proved effective in the treatment of several murine models of human genetic diseases. However, in scaling up to large animal models, intraperitoneal Implantations of these microcapsules in canines were associated with excessive Inflammatory response and rapid degradation. We now show that subcutaneous implantation of microencapsulated cells in canines is effective in delivering recombinant product systemically for extended periods, provides a surgically benign site, leads to less inflammatory response, and permits longer-term survival of microcapsules. Allogeneic MDCK cells engineered to secrete human growth hormone (hGH) were microencapsulated in alginate-poly-L-lysine-alginate and implanted subcutaneously. Systemic delivery of hGH was evident within 4 hours and peaked by day 1 after implantation in all dogs. The gradual decline of hGH in the circulation in the first 2 weeks coincided with the development of anti-hGH antibodies by day 11. The high titer persisted for more than 1 month, demonstrating indirectly the persistent delivery of hGH. Microcapsules retrieved from the subcutaneous implant maintained their structure throughout the experiment and were free of host cellular adhesions. The mechanical integrity of the subcutaneously implanted microcapsules also appeared superior to that of the intraperitoneal implant. Hence the subcutaneously implanted microcapsules required minimal surgical intervention and led to a low level of inflammatory response, and the implant survived for at least 1 month, thus demonstrating the feasibility of systemic delivery of recombinant products via subcutaneous implantation in large animals.
Stockley
T L
TL
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Robinson
K E
KE
Delaney
K
K
Ofosu
F A
FA
Chang
P L
PL
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D017690:Cell Transplantation / Q000502:physiology*; D062109:Dermatologic Surgical Procedures; D004285:Dogs; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007668:Kidney / Q000166:cytology*; D010529:Peritoneal Cavity / Q000166:cytology / Q000502:physiology / Q000601:surgery*; D012867:Skin / Q000166:cytology / Q000378:metabolism
D013006:Growth Hormone