Cystic fibrosis (CF) is a common autosomal recessive disease caused by mutations in the gene encoding CFTR. Currently, lung disease is the source of the major morbidity and mortality. Mutations in the gene encoding CFTR cause a loss of functional Cl- channels from the apical membrane of airway epithelia. This abnormality impairs mucociliary clearance and leads to the progressive airway disease and lung destruction. Despite improvements in the care of patients with CF, currently no treatment is directed at the underlying defect. The feasibility of gene transfer to treat CF was first demonstrated by the finding that expression of CFTR in airway epithelia corrected the Cl- transport defect. Thus, gene transfer to correct the molecular defect would represent a major advance in CF treatment; that is the major goal of this program. One major focus of the program is on the development and evaluation of adenoviral vectors to express CFTR in the airway epithelium. We propose studies in in vitro model systems and in animals that are designed to assess the efficacy and safety of adenoviral vectors. Based on our encouraging results to date, we also propose to test the adenoviral vector in humans with CF. To assess efficacy of gene transfer in the treatment of lung disease, we propose the development of new assay techniques using high resolution thin section computed tomography of the lung. Because effective gene transfer for the treatment of CF may require treatment of patients before lung disease develops, we also explore the use of retroviral vectors for somatic cell gene transfer to the airway epithelium of fetuses and neonates. In addition to the use of adenoviral vectors we explore a novel nonviral vector delivery system using folate/DNA conjugates. In collaboration, we are also developing adeno-associated viral (AAV) vectors. The results of the studies proposed in this program should enhance our knowledge about the factors required to successfully treat CF airway disease by gene transfer. The studies will also directly assess the efficacy and safety of gene transfer to treat CF. In addition, the services of the Vector and Morphology Cores should attract new investigators to use gene transfer for the treatment of CF and other diseases of the heart, lung, and blood.
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