Acute Responses of Non-Human Primates to Airway Delivery of an Adenovirus Vector Containing the Human Cystic Fibrosis Transmembrane Conductance Regulator cDNA

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Abstract
Recombinant human adenovirus (Ad) vectors are leading candidates for human gene therapy for cystic fibrosis (CF) based on demonstration of efficient transfer of exogenous genes to rodent respiratory epithelium in vivo and human respiratory cells in vitro. The safety of Ad-mediated gene transfer to the respiratory epithelium and acute (up to 21 days) clinical responses to airway delivery of a replication-deficient recombinant, E1¯, E3¯ Ad type 5-based vector containing the human cystic fibrosis transmembrane conductance regulator cDNA (AdCFTR) were evaluated in rhesus monkeys. Airway delivery of an Ad vector with the lacZ marker gene demonstrated β-galactosidase expression in epithelial cells. Animals administered intratracheal AdCFTR demonstrated human CFTR cDNA expression in airway epithelial cells. Animals administered AdCFTR intranasal, and 24 hr later, intrabronchial [2 × 107 to 5 × 1010 plaque-forming units (pfu), n = 12], in a fashion similar to a proposed human protocol, or only intrabronchial (1011 pfu, n = 3), had no significant changes in clinical parameters compared to vehicle controls (n = 6). Microscopic analysis of the lung by necropsy or bronchoalveolar lavage demonstrated a dose-dependent increase in inflammatory cells, primarily lymphocytes, in the area where AdCFTR was delivered, which persisted for at least 2 months in some animals. Serum anti-Ad type 5 neutralizing antibody titers did not rise and shed Ad was not detected. The presence of AdCFTR DNA, analyzed by the polymerase chain reaction (PCR), was not detected in organs outside the lung. These data demonstrate that AdCFTR is well tolerated in non-human primates, although there is dose-dependent inflammation in the lung not clinically apparent. This suggests that delivery of Ad vectors for human gene therapy may be dose limited. Adenovirus (Ad) vectors are leading candidates for gene therapy of cystic fibrosis (CF) lung disease. The safety of airway delivery of a recombinant, replication-deficient Ad vector containing the cystic fibrosis transmembrane conductance regulator cDNA (AdCFTR) was evaluated in non-human primates given increasing doses of the vector. Following single administration of AdCFTR to the airway, gene transfer was demonstrated and no clinical changes were observed. At necropsy, dose-dependent inflammation, confined to the area of AdCFTR delivery, was seen in the lung. This suggests that the use of Ad vectors for gene therapy of CF may be dose limited.