Correction of the Growth Defect in Dwarf Mice with Nonautologous Microencapsulated Myoblasts—An Alternate Approach to Somatic Gene Therapy

Abstract

Most of the currently approved human gene therapy protocols depend on genetic modification of autologous cells. We propose an alternate and potentially more cost-effective approach by implanting genetically modified “universal” cell lines to deliver desired gene products to nonautologous recipients. The recombinant allogeneic cells are protected from rejection after implantation by enclosure within immuno-protective alginate-poly-l-lysine-alginate microcapsules. The clinical efficacy of this strategy is now demonstrated by implanting microencapsulated allogeneic myoblasts engineered to secrete mouse growth hormone into the growth hormone-deficient Snell dwarf mice. The treated mutants attained increases in linear growth, body weights, peripheral organ weights, and tibial growth plate thickness significantly greater than those of the untreated controls. Secondary response to the exogenous growth hormone stimulation also resulted in increased fatty acid metabolism during the first month post-implantation. The microcapsules retrieved after about 6 months of implantation appeared intact. The encapsulated myoblasts retained a viability of >60% and continued to secrete mouse growth hormone. Thus, implantation of nonautologous recombinant cells corrected partially the pleiomorphic effects of a transcription factor mutation in the Snell dwarf mice and the encapsulated cells remained functional for at least 6 months. This simple method of delivery recombinant gene products in vivo is a benign procedure, obviates the need for patient-specific genetic modification, and is amenable to industrial-scale quality control. It should have wide applications in therapies requiring a systemic continuous supply of recombinant gene products.

Overview summary

“Nonautologous somatic gene therapeutics” is an alternate approach to somatic gene therapy in which universal cell lines engineered to secrete desired gene products are implanted into different recipients with the same product requirement. To prevent immune rejection of nonautologous cell lines, immuno-protective devices such as microcapsules are used to enclose these cells before implantation. We have succeeded in delivering recombinant gene products such as human growth hormone, human factor IX, and a secretable form of human adenosine deaminase in vitro and in vivo through this technology. We now show that this strategy is clinically effective. By delivering encapsulated myoblasts secreting mouse growth hormone to the growth hormone-deficient Snell dwarf mice, we have been able to enhance growth of these mutants as measured with a variety of physiological parameters. The possibility of delivering biologically active gene products in vivo for extended periods with a benign and potentially cost-effective protocol is useful not only for therapeutic purposes but also for studying developmental biology in some instances as an alternate to the transgenic animal paradigm.