Non-viral methods of gene transfer to airway epithelium

The airway epithelium has been an important target for gene therapy in the last decade. This route of administration is readily accessible and the airway is affected by a number of disorders for which gene therapy may be useful. Viral vectors were first used to transfer genes to the airway of cystic fibrosis patients a decade ago. However, in vivo results have been disappointing, with substantial inflammation and toxicity occurring at doses that do not produce significant gene transfer. More recently researchers have used plasmid DNA based technologies as an alternative. DNA alone can transfect cells in culture and in vivo, though it is inefficient. Complexing DNA with cationic molecules improves efficiency. Nonviral gene transfer with lipid-DNA complexes has showed promise in cell culture and animals, but is much less efficacious in humans, and inflammation occurs at doses below those required for therapeutic effect. Trans-nuclear membrane delivery appears to be the limiting factor of current liposome-DNA complex efficiency in vivo. DNA compacted with polycations has also been used with good success in animal models, with minimal toxicity and is currently being tested in human trials. In this review, we will discuss the advances and limitations of these nonviral vectors in gene delivery, particularly to airway epithelial cells.