Efficient gene regulation by PPARγ and thiazolidinediones in skeletal muscle and heart

We have developed a new gene regulation system for gene therapy. This system consists of two expression cassettes; one expresses the human peroxisome proliferator-activated receptor gamma (PPARgamma), and the other expresses the therapeutic gene under the control of multiple peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) linked to a basal promoter. Using direct injection of plasmid DNA into skeletal muscle or myocardium of rodents and oral administration of clinically approved PPARgamma activators, we demonstrate that reporter gene expression can be induced more than 25-fold. We show that oral administration of PPARgamma activator at intervals separated by several months results in repeated pulses of high-level reporter gene expression. We also document a PPARgamma activator dose-response effect on reporter gene expression. This is the first report of a gene regulation system that makes use of a human transcription factor and that may be safer than chimeric transcription factors for human gene therapy.