TRANSFER OF THE CFTR GENE TO THE LUNG OF NONHUMAN-PRIMATES WITH E1-DELETED, E2A-DEFECTIVE RECOMBINANT ADENOVIRUSES - A PRECLINICAL TOXICOLOGY STUDY

This paper describes a preclinical toxicology study designed to investigate the biological efficacy and safety profile of second-generation adenovirus for CFTR gene transfer into the baboon lung, This second-generation virus is deleted of El and contains a temperature-sensitive mutation in the E2a gene, which encodes a defective DNA-binding protein, Two distinct projects were undertaken, Group A animals received a first-generation adenovirus (i.e., deleted of El) in an upper lobe at the time a second-generation virus was instilled into the contralateral upper lobe, The goal of study A was to compare the biology of each construct directly and to determine if an immune response to the first-generation virus affected the performance of the second-generation virus, Group B animals received a lacZ second-generation virus in an upper lobe at the same time the CFTR second-generation virus was instilled in the other upper lobe, Necropsies were performed 4 or 21 days after gene transfer and tissues were evaluated for recombinant gene expression and histopathology, Using a second-generation adenovirus, recombinant gene stability was prolonged and associated with a diminished level of perivascular inflammation as compared to first-generation vectors, Markedly diminished levels of hexon protein were present in tissues infected with second-generation as compared to first-generation virus, No evidence of viral shedding was evident, Furthermore, coadministration of first- and second-generation adenovirus did not affect the stability of transgene expression from the second-generation virus, These data suggest that second-generation adenoviral vectors provide an improved gene delivery vehicle, and thus may be useful in gene therapy for cystic fibrosis.