Ja. Stgeorge et al., BIOLOGICAL RESPONSE OF NONHUMAN-PRIMATES TO LONG-TERM REPEATED LUNG EXPOSURE TO AD2 CFTR-2/, Gene therapy, 3(2), 1996, pp. 103-116
We have assessed the safety and efficacy of repeated adenovirus vector
administration by exposing the left caudal lung lobe of rhesus monkey
s to as many as 17 exposures of ad2/CFTR-2. After nine doses of either
3x10(9) infectious units, the monkeys were free of adverse effects as
assessed by thoracic radiographs, CBCs, clinical chemistries, arteria
l blood gases, and physical and clinical signs. In some animals elevat
ed protein levels and increased numbers of cells were recovered in bro
nchoalveolar lavage (BAL), and in all animals there were increased pro
portions of lymphocytes in the BAL. After 11 doses, two animals were k
illed. In the lower dose animal (3x10(9) IU), there was little histpat
hology evident. In the higher dose animal (3x10(10) IU), histopatholog
y was largely confined to a focal fibrotic lesion that may have been a
ssociated with treatment. At the tenth exposure, the dose was increase
d to 6x10(10) or 3x10(11) IU. There was evidence of lung injury by tho
racic radiographs after two additional exposures and an increase in pr
otein and number of cells in the BAL. The animals were still free of e
vidence of adverse effects by other parameters, but histopathologic ch
anges were notes upon death. After 15 or 17 doses, three animals were
instilled with Ad2/beta gal-2 and killed 3 days later. These animals h
ad greatly reduced levels of transgene expression when compared with c
ontrols.