Lung Gene Therapy: In Vivo Adenovirus-Mediated Gene Transfer to Rhesus Monkey Airway Epithelium

Publisher Website
Google Scholar
Abstract
Somatic gene therapy of lung disorders such as cystic fibrosis (CF) aims at introducing the therapeutic gene into respiratory epithelium. We have tested the ability of recombinant human adenovirus to infect rhesus monkey airway epithelium in vivo. Application of adenovirus harboring the lacZ marker gene to the airway surface resulted in large patches of lacZ-positive cells in the trachea, bronchi, and bronchioles, 6 days after virus exposure, indicating a successful transfer of the lacZ gene to respiratory epithelium. Microscopic analysis showed that basal, mucous goblet, and ciliated cells were lacZ positive. In addition, gene transfer to the submucosal glands was observed. Pathological examination of the organs revealed no virus-mediated toxic effects to the lungs and other organs. Using polymerase chain reaction (PCR) analysis we found no spread of the virus to blood or any organ tested. These results indicate the potential use and safety of adenoviruses as a tool in human gene therapy procedures aimed at pulmonary diseases. Direct gene transfer to airway epithelium is a prerequisite to bring about lung gene therapy. One possibility in this respect is to utilize replication-deficient recombinant adenovirus. This study describes the administration of recombinant human adenovirus harboring the lacZ marker gene to rhesus monkey lungs in vivo. This resulted in transfer and expression of the lacZ gene in different cell types of the airway epithelium. No pathological side effects were observed and no spreading of virus to organs other than the lungs was detectable. These observations underline the potential of adenoviruses as tools for gene therapy of lung disorders.