Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons.
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.
Morral
Núria
N
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
O'Neal
Wanda K
WK
Rice
Karen
K
Leland
M Michelle
MM
Piedra
Pedro A
PA
Aguilar-Córdova
Estuardo
E
Carey
K Dee
KD
Beaudet
Arthur L
AL
Langston
Claire
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects*; D005822:Genetic Vectors / Q000633:toxicity*; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010215:Papio; D010976:Platelet Count; D013921:Thrombocytopenia / Q000139:chemically induced; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D001616:beta-Galactosidase