CAR-binding Ablation Does Not Change Biodistribution and Toxicity of Adenoviral Vectors

Gene Ther. 2001 Sep;8(17):1347-53. doi: 10.1038/sj.gt.3301515.

Abstract

Intravenous administration of adenoviral vectors results mostly in hepatocyte transduction and subsequent hepatotoxicity. Because hepatocytes express high levels of the primary adenovirus receptor CAR, untargeting hepatocytes requires CAR-binding ablation. The amino acid residues of the viral fiber responsible for CAR-binding are known. We have constructed a mutant adenoviral vector unable to bind CAR and studied vector biodistribution and hepatotoxicity after intravenous administration. In contrast to a vector with wild-type fiber, the infectivity of the CAR-ablated vector is greatly reduced and not susceptible to inhibition with wild-type knob. Biodistribution and hepatotoxicity are, however, not affected by CAR-binding ablation. A possible explanation could be related to an increased blood persistence detected for the CAR-ablated vectors combined with their residual infectivity through other receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism*
  • Animals
  • Antibodies, Viral / metabolism
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Gene Expression
  • Genetic Vectors / metabolism*
  • Genetic Vectors / toxicity
  • Green Fluorescent Proteins
  • Hepatocytes / virology*
  • Injections, Intravenous
  • Luminescent Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Protein Binding
  • Receptors, Virus / immunology
  • Receptors, Virus / metabolism*
  • Tissue Distribution

Substances

  • Antibodies, Viral
  • CLMP protein, human
  • CLMP protein, mouse
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Luminescent Proteins
  • Receptors, Virus
  • Green Fluorescent Proteins