Aerosol Administration of a Recombinant Adenovirus Expressing CFTR to Cystic Fibrosis Patients: A Phase I Clinical Trial

Ad CFTR, a replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator (CFTR), was administered by aerosolization in a single escalating dose to three pairs (cohorts) of cystic fibrosis (CF) patients. Buffer only was administered to the nose and lungs 9–14 days before nasal instillation of virus followed the day after by aerosolization of Ad CFTR to the lung. Nasal doses (defined in terms of viral plaque forming units, pfu) were 10⁵, 10⁷, and 4 × 10⁸, whereas aerosolized doses were 10⁷, 10⁸, 5.4 × 10⁸ for each cohort, respectively. No acute toxic effects were observed in the first 4 weeks after virus treatment. Shedding of infectious Ad CFTR was never detected, whereas detection of vector DNA sequences and CFTR expression demonstrated DNA transfer to the nose and airways of patients. No significant deviations in immunological and inflammatory parameters were observed in serum and in bronchoalveolar lavage (BAL). Importantly, for all patients, the serum anti-adenovirus antibody levels did not change significantly from baseline and no antibodies against adenovirus were found in BAL.

Overview summary

Experimental evidence has shown that an adenovirus containing the cystic fibrosis transmembrane conductance regulator (CFTR) cDNA (Ad CFTR) can deliver a functional CFTR to airway epithelia, thus supporting the concept of gene therapy as a means to treat or even prevent the respiratory manifestations of cystic fibrosis (CF). We have consequently conducted a clinical trial involving 6 CF patients to determine the safety and biological efficiency of Ad CFTR when aerosolized to the lungs. This mode of administration may be a candidate treatment for CF by recombinant adenovirus.