L. A. Davies, S. C. Hyde and D. R. Gill
DNA Pharmaceuticals, 145-164 (3-527-31187-4)
Gene transfer to the airways is being investigated as a possible therapy for a variety of acute and chronic lung diseases such as cancer, cystic fibrosis and emphysema. Lung gene transfer is also being developed for applications such as the prevention of lung transplant rejection and the treatment of lung damage following radiotherapy. The lung is a complex organ containing multiple cell types. The tracheobronchial tree extends from the trachea down through numerous divisions of airways lined with epithelium. In the larger airways the epithelium is pseudostratified, consisting mainly of ciliated and non-ciliated columnar cells, goblet cells and a layer of basal cells; the epithelium eventually transitions to a single layer of cells lining the respiratory bronchioles. The parenchyma of the lung contains the gas-exchanging alveolar cells and is highly vascularized with capillary endothelial cells. Therapeutic gene transfer will require gene expression in the appropriate cell types of the lung, which can be achieved by judicious selection of the gene transfer agent (GTA). Viral vectors transduce cells depending on receptor specificity and availability for uptake, although this may be modified by manipulation of the virus pseudotype. Following gene transfer to the lung, several viral GTAs have resulted in debilitating immune and inflammatory responses limiting the options for repeated administration of these vectors. Recently there has been increased interest in the use of non-viral, plasmid-based GTAs that can be manipulated to transfect a wide range of lung cell types. In addition to the use of naked plasmid DNA (pDNA), plasmids may also be complexed with a variety of lipids, polymers and polycations and many of these have been evaluated following delivery to the lung.