Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993

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Revision as of 19:11, 7 March 2010

Abstract

• Prepared a pre-clinical 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 ~-galactosidase (lacZ) were instilled through a bronchoscope into limited regions of lung in 14 baboons
• Results of toxicity studies were found using clinical laboratory tests, chest radiographs, and necropsy tests were used
  • These 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 and 107 and 108 pfu (plaque forming units) per ml (infectious units per volume) but perivascular lymphocytic and histocytic infiltrate was seen at 109 and 1010
    • Intensity of inflammation increased between 4 and 21 days
      • At its greatest intensity, there was diffuse alveolar wall damage with intra-alveolar edema (the airways were relatively spared)
  • Chest radiographs revealed alveolar infiltrates, but only in regions of lung having the greatest intensity inflammation
• Concluded that adenovirus-mediated gene transfer into the lungs of baboons is associated with development of alveolar inflammation at high doses of virus

Introduction

• Adenovirus-base vectors have certain properties that make them attractive vehicles for human gene therapy
  • Ability to transfer genetic material efficiently into lung epithelial cells
    • Led them to be chosen for the first trials for human gene therapy for cystic fibrosis
• Success of trial will be determined by the level and duration of transgene expression and safety
  • Performed studies on baboons in order to prepare for human trial