High efficiency intramuscular plasmid electrotransfer: application for sustained plasmatic secretion of cytokines

Gene delivery to skeletal muscle and to tumors is a promising strategy for the treatment of muscle disorders or cancer, and for the systemic secretion by muscle of therapeutic proteins. We and others have reported efficient plasmid DNA transfer into muscle fibers using square-wave electric pulses of low field strength and of long duration [1,2,3,4,5]. This i.m. plasmid 'electrotransfer' method increases reporter and therapeutic gene expression by several orders of magnitude in various muscles and species, and decreases inter-individual variability. We will present recent results concerning the plasmatic secretion after i.m. gene electrotransfer of a reporter protein, human secreted alkaline phosphatase, which was sustained for more than 12 months. Factor IX was also detected at high concentration in the systemic circulation after i.m. plasmid electrotransfer. Intramuscular electrotransfer of an EPO-encoding plasmid led to a several-months stable hematocrit increase. Moreover, EPO seretion also led to phenotoypic correction in a murine model of beta-thalassemia. Finally, electrotransfer of a murine IL-10-encoding plasmid was shown to induce a significative, but transient increase in circulating IL-10. This had a protective role in atherosclerosis, achieving 60 % reduction in lesion size, and also modulated VEGF expression and neoangiogenesis in a model of hindlimb ischemia.