CONTROLLABLE GENE-THERAPY - PHARMACEUTICS OF NONVIRAL GENE DELIVERY SYSTEMS

Although most research on gene therapy has focused on the development of viral-mediated approaches to deliver therapeutic genes to cells bot h ex vivo and in vivo, non-viral gene medicines have emerged as a pote ntially safe and effective gene therapy method for the treatment of a wide variety of acquired and genetic diseases. Gene medicines consist of bath a gene expression system that contains a therapeutic gene and a synthetic gene delivery system. Gene expression systems can be const ructed to control the location, amount and duration of in vivo product ion of a therapeutic protein. A gene delivery system controls the dist ribution and access of a gene expression system to a target tissue, it s recognition by cell-surface receptors and its intracellular traffick ing. As each biological target will require a unique gene delivery and gene expression system, many of the principles and methods establishe d in developing advanced drug delivery systems can be applied to the d esign and preparation of synthetic gene delivery systems. This paper d escribes different approaches taken to protect and to enhance the deli very of gene expression systems to target cells. Self-assemblies of co ndensing carriers, such as cationic liposomes, synthetic polymers and peptides, with a gene expression system are described. The characteriz ation of the resulting particulate gene medicines is reported, as is t he influence of their physicochemical properties on the efficiency of gene delivery. This contribution also describes approaches to effect t he intracellular trafficking of a gene expression system to the nucleu s of a target cell, in particular by using synthetic amphipathic pepti des to control the endosomal release of plasmid DNA.