Readministration of helper-dependent adenovirus to mouse lung

Abstract

Adenovirus vectors (Ad) are widely used in gene therapy studies, including those aimed at treating cystic fibrosis lung disease. Various approaches have been investigated to blunt the host immune response to Ad, including development of helper-dependent (HD) Ad. The host cytotoxic T-cell response to HD-Ad is generally lower than to earlier-generation Ad. However, antibodies are formed which could inhibit the efficacy of HD-Ad readministration. In this first study of HD-Ad readministration to the lung, we found that a second administration of HD-Ad to mice was possible with minimal loss of transgene expression. In contrast, when first-generation (FG) Ad was administered initially, followed by HD-Ad or FG-Ad, transgene expression was reduced. Significantly lower concentrations of antibodies against Ad were found in lung lavage fluid and serum from mice that received two doses of HD-Ad (when the initial HD-Ad lacked a transgene), compared to mice that received FG-Ad followed by HD-Ad. These data suggest that readministration of HD-Ad for lung gene therapy may be feasible.