Regulated gene expression in encapsulated cells

The treatment of human diseases is more and more approaching the molecular level. In this concept, gene therapy has a high potential for curing both inherited and acquired diseases. The strategies range from the simple replacement of missing gene functions to subtle interference with misregulated biochemical and genetic pathways. A critical step of the technique is the introduction of the artificial genes into the host genome. In cell therapy, the problems associated with random integration of the DNA are avoided by transplanting transgenic cells into the patient, which are protected from the host immune system by a semipermeable membrane or capsule. Such encapsulated cells have the potential to produce an array of gene products. Current approaches for gene- or cell therapy are mainly based on continuous expression of peptides, but as for most pharmacologically active substances, a regulation of the dosage would be desirable. We present here a strategy to manipulate the level of transgene expression in transplanted, encapsulated cells by magnetic fields. For this purpose we will generate cells in which the transgene is under control of a heat inducible promoter, which are in turn encapsulated together with magnetic nanoparticles. After transplantation of the capsules into the tissue of the patient, an externally applied magnetic field will activate the particles in the capsules. The resulting elevated temperature will induce the heat shock promoter and initiate transgene expression. Thus the patient could self-regulate expression of the therapeutic agent in the body by applying a defined external magnetic field. In this project we plan to establish the method in a cell culture system, improve the expression characteristics of the promoter and finally provide a first proof-of- principle for the method in mice.

The treatment of human diseases is more and more approaching the molecular level. In this concept, gene therapy has a high potential for curing both inherited and acquired diseases. The strategies range from the simple replacement of missing gene functions to subtle interference with misregulated biochemical and genetic pathways. A critical step of the technique is the introduction of the artificial genes into the host genome. In cell therapy, the problems associated with random integration of the DNA are avoided by transplanting transgenic cells into the patient, which are protected from the host immune system by a semipermeable membrane or capsule. Such encapsulated cells have the potential to produce an array of gene products. Current approaches for gene- or cell therapy are mainly based on continuous expression of peptides, but as for most pharmacologically active substances, a regulation of the dosage would be desirable. We present here a strategy to manipulate the level of transgene expression in transplanted, encapsulated cells by magnetic fields. For this purpose we will generate cells in which the transgene is under control of a heat inducible promoter, which are in turn encapsulated together with magnetic nanoparticles. After transplantation of the capsules into the tissue of the patient, an externally applied magnetic field will activate the particles in the capsules. The resulting elevated temperature will induce the heat shock promoter and initiate transgene expression. Thus the patient could self-regulate expression of the therapeutic agent in the body by applying a defined external magnetic field. In this project we plan to establish the method in a cell culture system, improve the expression characteristics of the promoter and finally provide a first proof-of- principle for the method in mice.