Efficient Adenovirus-Mediated Gene Transfer to Basal but Not Columnar Cells of Cartilaginous Airway Epithelia

Publisher Website
Google Scholar
Abstract
Adenoviral vectors (AdV) developed for treatment of the pulmonary manifestations of cystic fibrosis (CF) can deliver, with high efficiency, transgenes to respiratory epithelial cells grown in culture. This study investigated the efficiency of AdV-mediated gene transfer to murine and human respiratory epithelium in vivo and concluded that the epithelial cells facing the lumen of the respiratory cartilaginous airways (columnar cells) are poorly transduced with AdV. Mechanical injury to the epithelium, however, leads to efficient in vivo gene transfer by exposing a susceptible epithelial subtype (basal cells). Increased gene transfer efficiency in vivo after injury is not a nonspecific response because the proliferative status of the epithelium after injury was shown not to correlate temporally to the increased transduction susceptibility of the epithelium. Although basal cells were the cell type transduced at the time of vector delivery, with time, basal cell differentiation to columnar cells occurred with maintenance of transgene expression. Collectively, these results show that murine and human cartilaginous airways are poorly transduced by AdV. To correct the cartilaginous airway CF bioelectrical defect in vivo, efforts should be directed to increase the tropism of AdV to the columnar airway epithelial cells. Adenoviral-based vectors (AdV) are the most widely tested vectors for the treatment of the pulmonary manifestations of cystic fibrosis (CF) by gene therapy. The target cell for correction within the epithelium that lines the conducting airways of the lung is the columnar cell. However, we show here with mouse and human species that the columnar component of the epithelium extending into the cartilaginous bronchial regions is resistant to AdV transduction. Injury of the epithelium promotes gene transfer, primarily by exposing susceptible basal cells to vector rather than via nonspecific cellular responses to repair. These results suggest that emphasis should be directed to increasing the tropism of AdV to the columnar airway epithelial cells to achieve efficient gene transfer to the cartilaginous airways.