[Gene transfer to airway epithelial cells: current status and future direction]

Advances in recombinant DNA technology and molecular and cellular biology have made it feasible to introduce genes into living cells. The most sophisticated gene transduction methods have bee applied to gene therapy strategies for the potential treatment of genetic diseases. In regard to lung diseases, alpha 1-antitrypsin deficiency and cystic fibrosis, the most common hereditary lung disorders in Caucasians, have been targeted for gene therapy. To date, gene therapy studies have been confined to ex vivo strategies for treatment of ADA deficiency with retroviral vectors. However, there are two major obstacles to gene transfer to the bronchial epithelium. First, bronchial epithelium, such as that with ciliated cells, is terminally differentiated, and does not divide rapidly. Second, the complex architecture of the lung precludes replacing the existing bronchial epithelium with cells modified by gene transfer. In the context of these properties of bronchial epithelium, adenovirus vectors have been evaluated for direct introduction of therapeutic genes to bronchial epithelium via the airway in vivo. An in vivo experiment revealed that gene transfer with a replication-deficient adenovirus containing the E. coli lacZ (beta-galactosidase) gene driven by cytomegalovirus promoter (AdCMVlacZ) was 10(4) times more efficient than gene transfer with a plasmid containing the same expression cassette (pCMVlacZ). An experiment based on in vitro data was done to evaluate the distribution of the expression of the exogenous genes transferred by adenovirus vectors. Intratracheal administration of AdCMVlacZ into lungs of experimental animals resulted in a high number of beta-gal-positive epithelial cells in bronchiols, rather than in proximal bronchi. Thus, a replication-deficient adenovirus can be used to transfer exogenous genes to airway epithelial cells in vivo. This technique may be useful in gene therapy for cystic fibrosis. Gene transfer can be thought of as the use of genetic information to modity the milieu of the target organ. In addition, gene transfer may allow the introduction of new genes, or the alteration tion of existing genes in intact animals. Gene transfer could them be used to produce animal models of human lung diseases that are particularly difficult to study.