Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons

Hum Gene Ther. 2002 Jan 1;13(1):143-54. doi: 10.1089/10430340152712692.

Abstract

The effects of intravenous administration of a first-generation adenoviral vector expressing beta-galactosidase were compared in two baboons receiving a high dose or lower dose of vector, 1.2 x 10(13) or 1.2 x 10(12) particles/kg, respectively. The high-dose baboon developed acute symptoms, decreased platelet counts, and increased liver enzymes, and became moribund at 48 hr after injection, while the lower-dose baboon developed no symptoms. Expression of the beta-galactosidase transgene was prominent in liver, spleen, and endothelium of the arterial vasculature in the high-dose baboon, but was much more limited and spared the endothelium in the lower-dose baboon. Injury to the vascular endothelium was the most prominent abnormality in the high-dose baboon. Extensive histological studies provide a detailed picture of the pathology associated with a lethal dose of first-generation adenoviral vector in a primate.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Endothelium, Vascular / drug effects*
  • Genetic Vectors / toxicity*
  • Infusions, Intravenous
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Papio
  • Platelet Count
  • Thrombocytopenia / chemically induced
  • Tissue Distribution
  • Tumor Necrosis Factor-alpha / metabolism
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • Interleukin-6
  • Interleukin-8
  • Tumor Necrosis Factor-alpha
  • beta-Galactosidase