Delivery of Recombinant Gene Products with Microencapsulated Cells In Vivo

Abstract

If established cultured cell lines genetically modified to secrete desired gene products could be implanted in different allogeneic recipients without immune rejection, novel gene products would be delivered more cost effectively. We tested this strategy by encapsulating mouse Ltk¯ cells transfected with the human growth hormone (hGH) gene in immunoprotective permselective alginate microcapsules. Allogeneic mice implanted with these microcapsules demonstrated hGH in their circulation (0.1–1.5 ng/ml serum) within the first 2 weeks. Control mice implanted with only the transfected cells without microcapsules did not demonstrate significant levels of circulating hGH. By about 3 weeks, antibodies against hGH developed in the microcapsule-implanted mice. The immune response was detected only against the hGH and no other secretory products from the transfected cells. The antibody titer continued to escalate for more than three months, thus demonstrating indirectly the continued delivery of the growth hormone. The persistent expression of the transgene and survival of the transfected cells were verified when the microcapsules were retrieved periodically to demonstrate that the encapsulated cells remained viable, proliferative, and productive of hGH even by 78–111 days. In conclusion, delivering gene products with genetically modified allogeneic cells in vivo has been shown feasible for prolonged periods. This technology should have potential applications in somatic gene therapy and in treatment of other somatic diseases. This paper describes the feasibility of an alternative approach to somatic gene therapy in which a standard cell line engineered to secrete a desired gene product may be implanted in different allogeneic recipients. To prevent graft rejection, the cells can be protected by permselective membranes, which permit the exit of the secreted novel gene product but not the entry of cellular immune mediators. It is now shown that such encapsulated mouse fibroblasts could survive and proliferate for over 3 months after implantation and continued to express a transgene coding for human growth hormone. This work demonstrates the feasibility of using non-autologous cells for somatic gene therapy, thus circumventing the need to modify genetically the patient's own cells. This may be a more cost-effective approach to delivering novel gene products in vivo and have potential applications in veterinary and human medicine.