Delivery of Recombinant Gene Product to Canines with Nonautologous Microencapsulated Cells
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abstract
An alternative and potentially cost-effective approach to somatic gene therapy is to engineer a universal cell line secreting the desired product suitable for implantation into different patients without immune rejection. Encapsulating these cells in immunoprotective alginate microcapsules showed that this approach was effective in treating murine models of human diseases. We now report that this approach is also effective in delivering recombinant gene products to large animals. Canine MDCK cells encapsulated in alginate microcapsules were able to deliver recombinant human growth hormone to nonautologous dogs in vivo. However, the same microcapsules capable of prolonged delivery in mice soon disappeared after implantation in dogs. In contrast, when these microcapsules were modified by using a higher concentration of alginate cross-linked with barium instead of calcium, and by fabricating the alginate as a gelled bead without solubilizing the core, more prolonged and higher levels of recombinant product were obtained. Laminating the surface of the beads with poly-L-lysine and alginate provided an even more mechanically stable device that lasted for >2 months instead of <14 days in vivo and delivered >20 ng of human growth hormone/ml of plasma within the first week. The apparent disappearance of the growth hormone from the circulation after day 14 was due to rapid clearance by anti-human growth hormone antibodies and not due to loss of cell viability. However, all microcapsules provoked an inflammatory reaction, causing mild omentitis, and eventually disappeared from the intraperitoneal cavity. In conclusion, systemic delivery of recombinant gene products with nonautologous cells protected in alginate microcapsules has been shown to be feasible in canine recipients. While improved level and duration of delivery have been achieved by increasing the mechanical stability of the microcapsules, further improvements in biocompatibility and stability will be required for human application.
