Exploiting chromosomal and viral strategies: the design of safe and efficient non-viral gene transfer systems

The development of gene transfer systems for therapeutic applications depends, to a large part, on an understanding of chromosomal elements mediating controlled gene expression, and DNA synthesis and maintenance. The integration of transgenes into chromosomes assures their faithful replication and segregation due to the natural functions of the host chromosome, but their expression is susceptible to inactivation by the host-cell apparatus, and they may also cause unwanted mutagenic effects. While episomal vectors are free from these shortcomings, progress in this field suffers from the lack of an in-depth understanding of the accessory functions, although a number of first-generation prototypes have been constructed in the past years. As an immediate solution, small non-viral circular episomal vectors are emerging which not only permit the study of the relevant components in a minimal gene-transfer system, but for which a considerable potential for therapeutic applications can be anticipated.