Methods for adenovirus-mediated gene transfer to airway epithelium

Recombinant adenoviral vectors have proven to be extremely efficient tools for transferring genes into multiple organ systems including the lung (1-5), liver (6-10), muscle (11,12), joint (13), vasculature (14,15), and central nervous system (16-18). The lung presents unique advantages as a target organ for the evaluation of these vectors as tools for in vivo gene therapy owing to the accessibility of target cells by direct instillation or inhalation of recombinant virus in the airway. Multiple therapeutic applications of gene therapy to the lung include both inherited disorders such as cystic fibrosis (CF) and α-antitrypsin deficiency, as well as acquired disorders such as bronchitis, asthma, emphysema, and respiratory malignancies. The most widely studied application to date has involved the analysis of recombinant adenoviruses for gene therapy of CF lung disease (1-5). To this end, multiple phase I clinical trails are now underway evaluating the safety of recombinant adenoviral vectors for gene therapy of cystic fibrosis lung disease (19). This clinical application of these vectors in CF lung disease presents the largest comprehensive effort of in vivo gene therapy to date. Such a substantial effort has offered the advantage of multiple preclinical studies evaluating delivery of adenoviral vectors to the lung in numerous animal models such as the cotton rat (4,5,20), human bronchial xenografts (1), mouse (21), and nonhuman primates (2,3,22,23).