Cystic fibrosis (CF) is a common autosomal-recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a regulated Cl- channel. Mutations in the CFTR gene cause a loss of function of CFTR Cl- channels, thereby causing defective fluid and electrolyte transport by affected epithelia. In the airways, these abnormalities contribute to the pathogenesis and pathophysiology of the disease. Despite therapy directed at the symptoms of lung disease, CF is a lethal disease. No available therapy treats the basic CF defect. The feasibility of correcting the molecular defect by gene transfer was demonstrated when expression of CFTR in airway epithelia in vitro restored normal Cl- transport. To develop a method of in vivo gene transfer for humans, we have developed adenoviral vectors that encode CFTR. Our preliminary studies suggest that the adenoviral vector directs expression of CFTR in airway epithelium modeled in vitro and in vivo in cotton rats and monkeys. The goal of this project is to investigate adenovirus as a vector system, to address basic issues about the requirements for gene transfer to complement the Cl- transport defect in CF airway epithelia, and to evaluate safety of the adenoviral vector system.
The aims are: 1. Evaluate the efficacy of adenovirus as a vector for CF gene therapy. To address this issue, we will use adenoviral vectors encoding both beta- galactosidase, as a reporter, and CFTR. We will express these genes from several different promoters to address several questions. a) In what percent of cells does adenovirus direct recombinant protein expression? b) What percent of cells must express CFTR to complement the CF Cl- transport defect? c) Is correction of the CF fluid and electrolyte transport abnormalities dependent upon the amount of CFTR expressed per cell? d) What is the duration of adenovirus-directed protein expression? e) How can the adenoviral delivery system be optimized? 2. Safety of adenovirus as a vector for CF gene therapy. We will focus on two questions. a) What is the effect of overexpressing CFTR on fluid and electrolyte transport? b) What is the effect of repeated administration of adenovirus to the lung?
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