Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study

Hum Gene Ther. 1993 Dec;4(6):771-80. doi: 10.1089/hum.1993.4.6-771.


In preparation for human trials of gene therapy for cystic fibrosis (CF), we performed a preclinical study of gene transfer into the lungs of baboons. Recombinant adenovirus vectors containing expression cassettes for human cystic fibrosis transmembrane conductance regulator (CFTR) and Escherichia coli beta-galactosidase (lacZ) were instilled through a bronchoscope into limited regions of lung in 14 baboons. A detailed accounting of the extent, distribution, and duration of gene expression is contained in a companion article (Engelhardt et al., 1993b). In this article, we report the results of toxicity studies in which clinical laboratory tests, chest radiographs, and necropsy studies were used to detect adverse effects. The only adverse effect noted was a mononuclear cell inflammatory response within the alveolar compartment of animals receiving doses of virus that were required to induce detectable 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 perivascular lymphocytic and histiocytic infiltrate was seen. The intensity of inflammation increased between 4 and 21 days. At its greatest intensity, there was diffuse alveolar wall damage with intra-alveolar edema. Airways were relatively spared, despite the intensity of alveolar inflammation. Clinical tests did not accurately reflect the presence of lung 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 transfer into the lungs of baboons is associated with development of alveolar inflammation at high doses of virus.

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Blood Cell Count
  • Blood Chemical Analysis
  • Bronchoscopy
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Escherichia coli / enzymology
  • Genetic Therapy / adverse effects*
  • Genetic Vectors
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / therapeutic use
  • Membrane Proteins / toxicity
  • Papio
  • Pneumonia / diagnostic imaging
  • Pneumonia / etiology*
  • Pneumonia / pathology
  • Pulmonary Alveoli / pathology
  • Radiography, Thoracic
  • beta-Galactosidase / genetics


  • CFTR protein, human
  • Membrane Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • beta-Galactosidase