Towards a gene therapy for cystic fibrosis lung disease

Abstract

Gene therapy for the treatment of the pulmonary manifestations of cystic fibrosis (CF) has been at the forefront of gene therapy research over the last several years. During this time, however, despite immense efforts, controlled clinical trials with CF patients have failed to demonstrate significant and reproducible `correction' of the CF bioelectrical functional defect. The target tissue requiring `correction' in CF lung disease is the respiratory epithelium that lines the airways of the lung, and evidence is now emerging that the epithelium has evolved to elude the uptake of potential pathogens, including viruses, bacteria and gene transfer vectors. The majority of studies with gene transfer to the airway epithelium have used the adenovirus as the gene delivery vector, since high efficiency gene transfer to airway epithelial cells grown in culture can be demonstrated. However, when these vectors are tested in the airways of animals and humans in vivo, the efficiency of gene transfer is low. It is likely that these observations are not limited to adenoviral vectors (Ad), since similar gene transfer discrepancies are observed with a range of vector systems being developed for CF lung gene therapy. Therefore, this update will focus on the factors responsible for efficient gene transfer to airway epithelial cells in vitro and, using Ad as examples, discuss the development of `targeted' gene transfer vectors that may overcome the resistance of the airway epithelium in vivo to efficient gene transfer.