Cystic Fibrosis (CF), a common lethal hereditary disorder of Caucasians, is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a 250,000 bp, 27 exon gene on chromosome 7. The disorder is characterized by airway and gastrointestinal disease. The lung manifestations dominate, and 90% of individuals with CF die of respiratory complications. The pathogenesis of the airway disease is clearly linked to the mutations in the CFTR genes and the lack of sufficient CFTR function in the airway epithelium. Despite advances in therapy directed toward suppressing the infection and clearing the airways, CF almost invariably leads to respiratory insufficiency, with a median survival in the USA of 29 years. Following approval by the appropriate regulatory groups, the first human gene therapy trial for CF was begun on April 17, 1993. So far, the adenovirus vector containing CFTR cDNA (AdCFTR) has been administered to the respiratory epithelium of four CF individuals. The data demonstrate that an adenovirus vector is capable of in vivo transferring and expressing the CFTR cDNA in the respiratory epithelium of individuals with CF. With doses of 2x106 to 2x109 pfu administered to the bronchial epithelium, there was no evidence of recombination or complementation of the vector to produce a replication-competent adenovirus, shedding of the vector, or rise in titers of serum anti-adenovirus neutralizing antibodies. At the highest dose (2x109 pfu), there was a transient systemic and pulmonary syndrome likely secondary to local inflammation initiated by the vector in the lower respiratory tract. Despite this, 6 to 12 month follow-up of all four patients demonstrated no long-term adverse effects with lung function tests similar to pre-therapy values. In addition to gene therapy, AdCFTR has also been used for the study of CFTR function, which demonstrates that CFTR has functions other than that of a cAMP-regulated Cl- channel. In addition to CF, the gene therapy for acute lung injury using adenovirus vector containing surfactant cDNA has also been studied.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Intramural Research (Z01)
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National Heart, Lung, and Blood Institute
United States
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