Safety of Airway Gene Transfer with Ad2/CFTR2: Aerosol Administration in the Nonhuman Primate

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Abstract
In this study, the safety and efficacy of aerosol delivery to non-human primates of an adenoviral vector encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) were evaluated. The technique of concurrent flow spirometry was used to determine the deposited dose of Ad2/CFTR-2, which ranged from 3 to 8 × 1010 I.U. Transgene DNA was detected by the polymerase chain reaction (PCR) in lung tissue from all treated animals, and human CFTR mRNA was detected on days 3, 7, and 21 post-exposure. The treatment was well tolerated, with no evidence of respiratory distress. Histologic changes in the lungs from Ad2/CFTR-2-treated animals were mild and, overall, indistinguishable from animals exposed to aerosolized vehicle. One vector-treated animal demonstrated an increase in lavage lymphocyte numbers 3 days after treatment and another had an abnormal chest radiograph 14 days after treatment. A third vector-treated animal had histologic evidence of a bronchointerstitial pneumonia 7 days after aerosol treatment that resolved by day 21. This study demonstrated that Ad2/CFTR-2 can effectively be delivered to the lungs of nonhuman primates and result in minimal adverse effects. The safety of aerosol administration of Ad2/CFTR-2, an adenoviral vector of the human CFTR gene, was evaluated in rhesus monkeys. Ad2/CFTR-2 was administered by aerosol in spontaneously breathing animals, and the dose delivered to the lower airway was evaluated through concurrent flow spirometry. Treatment was well tolerated, and no immediate adverse effects were noted. Treatment-related findings were limited to minimal changes in the lung in some animals.