ADENOVIRUS-MEDIATED TRANSFER OF THE CFTR GENE TO LUNG OF NONHUMAN-PRIMATES - TOXICITY STUDY

In preparation for human trials of gene therapy for cystic fibrosis (C F), we performed a preclinical study of gene transfer into the lungs o f baboons. Recombinant adenovirus vectors containing expression casset tes for human cystic fibrosis transmembrane conductance regulator (CFT R) and Escherichia coli beta-galactosidase (lacZ) were instilled throu gh a bronchoscope into limited regions of lung in 14 baboons. A detail ed accounting of the extent, distribution, and duration of gene expres sion is contained in a companion article (Engelhardt et al., 1993b). I n this article, we report the results of toxicity studies in which cli nical laboratory tests, chest radiographs, and necropsy studies were u sed to detect adverse effects. The only adverse effect noted was a mon onuclear cell inflammatory response within the alveolar compartment of animals receiving doses of virus that were required to induce detecta ble gene expression. Minimal inflammation was seen at 10(7) and 10(8) pfu/ml, but at 10(9) and more prominently at 10(10) pfu/ml, a perivasc ular lymphocytic and histocytic infiltrate was seen. The intensity of inflammation increased between 4 and 21 days. At its greatest intensit y, there was diffuse alveolar wall damage with intra-alveolar edema. A irways were relatively spared, despite the intensity of alveolar infla mmation. Clinical tests did not accurately reflect the presence of lun g inflammation, with the exception of chest radiographs which revealed alveolar infiltrates, but only in regions of lung having the greatest intensity inflammation. We conclude that adenovirus-mediated gene tra nsfer into the lungs of baboons is associated with development of alve olar inflammation at high doses of virus.