10 Advances in Synthetic Gene-delivery System Technology

Abstract

Twenty-six years ago in a Science article, Friedmann and Roblin (1972) outlined prospects for human gene therapy. This forward-looking review anticipated the development of two alternative gene-delivery systems: viral-gene therapy vectors and synthetic gene-delivery systems using purified gene sequences. As molecular biology techniques matured, the tools to package genes into nonreplicating, recombinant viral vectors became available (Mann et al. 1983), allowing the efficient introduction of recombinant genes into living cells in vitro (cultured cells) and in vivo (animals and humans). During the last several years, we have witnessed an exponential growth in preclinical research and clinical development of recombinant viral vectors for gene-therapy applications. However, the introduction of synthetic, nonviral gene-delivery systems into the clinical gene-therapy repertoire took somewhat longer to develop.

Scientists at Vical, Inc. and the University of Wisconsin made a key discovery that led to increased interest in direct nonviral gene-transfer technology (Wolff et al. 1990). These investigators were the first to show that under certain conditions, muscle tissues could absorb plasmids, leading to expression of the encoded protein persisting for periods of weeks to several months. Improvements in this basic finding led to what has been referred to as “naked DNA” reagents for gene transfer. In addition, numerous laboratories and biotechnology companies are developing other technologies that allow the delivery of DNA directly into nonmuscle tissues, including the use of cationic lipid molecules that facilitate direct absorption of DNA into cells. The plasmids used for these products are chemically well defined and highly purified and can...