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

Abstract

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 10(5), 10(7), and 4 x 10(8), whereas aerosolized doses were 10(7), 10(8), 5.4 x 10(8) 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.

Formation of LID vector complexes in water alters physicochemical properties and enhances pulmonary gene expression in vivo

“…Initial clinical trials in cystic fibrosis, although promising, have highlighted the need to develop a safe and efficient vector system for pulmonary gene therapy to fulfil its potential. [5][6][7] The LID vector consists of a cationic liposome (L), an integrin-targeting peptide (I), with a 16 lysine tail, and plasmid DNA (D), combined in optimal proportions to form an electrostatic complex, which has previously been shown to efficiently transfect a number of cell types in vitro. 8 The LID vector efficiently transfected the lungs of rats mediated, at least in part, via the integrin-targeting component of the complex.…”

The extra- and intracellular barriers to lipid and adenovirus-mediated pulmonary gene transfer in native sheep airway epithelium

“…The two most widely used gene transfer systems are cationic lipids and adenoviruses, with both assessed in phase I studies of nasal and pulmonary delivery. [1][2][3][4][5][6][7][8] Results have been encouraging, though only limited correction of the CF bioelectric defect has been observed. With respect to the extent of gene transfer needed, a present best estimate might be approximately 5% of normal cystic fibrosis transmembrane conductance regulator (CFTR) mRNA levels within every cell, 9 complete correction of the chloride defect in approximately 5% of cells within the airway epithelium, 10 or likely some combination of the two.…”

Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice

“…Recombinant adenoviruses have been used to transfer the gene encoding CFTR in vitro and in vivo, and clinical trials are in progress at several major CF centers in the USA. [5][6][7][8][9][10] Several potential barriers to successful adenovirus-mediated gene transfer to the airways have been recognized which include the need for repeated delivery to maintain transgene expression, 11 the host inflammatory response to the vector, and specific immune responses to adenovirus vectors. [12][13][14] In vivo models used so far to conduct published studies of adenovirus-mediated gene transfer to the lungs have employed animals with uninfected, uninflamed lungs at the time of vector administration.…”