Influence of method of systemic administration of adenovirus on virus-mediated toxicity: Focus on mortality, virus distribution, and drug metabolism

Abstract

Doses of 2 × 1012 virus particles/kilogram (vp/kg) and higher of recombinant human adenovirus serotype 5 (HAdV-5) given via the tail vein induce significant toxicity and mortality in the rat. This was not observed when doses of 5.7 × 1012 vp/kg were given through a surgically implanted jugular catheter. Here we assess how the manner by which HAdV-5 is introduced into the systemic circulation affects biodistribution, transgene expression, toxicity and mortality 0.25, 1, and 4 days after treatment in the rat. Animals were given 5.7 × 1012 vp/kg of HAdV-5 expressing beta-galactosidase or saline through a jugular catheter or by direct tail-vein injection. All animals survived after jugular vein dosing. Tail-vein injection of HAdV-5 increased the mortality rate to 42% (p ≤ 0.01). All deaths occurred within 4 hours. Animals dosed through the jugular vein had significantly higher levels of transgene expression in the liver and spleen and significantly more viral genomes in these tissues and kidney and lung within the first 24 hours of viral infection compared to those dosed by tail-vein injection (p ≤ 0.01). There was no significant difference between the groups thereafter. Samples from animals that died contained even higher levels of viral genomes and serum transaminases were elevated on average by a factor of 4 at the time of death. There was no significant difference between the two dosing methods with respect to changes in hepatic cytochrome P450 expression and activity throughout the study. These findings suggest that the method of systemic administration should be carefully considered when assessing toxicity data and other parameters at early time points after virus administration in the rat and possibly other animal models.

Organ-specific shifts in mtDNA heteroplasmy following systemic delivery of a mitochondria-targeted restriction endonuclease

“…In rodents and non-human primates, systemic administration of rAd5 results in high transduction in liver 19 , 39 – 41 . In addition, jugular vein injection appears to increase survival compared to tail vein injection 42 .…”

Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

“…Cells were then overlaid with minimum essential medium (Gibco Invitrogen) containing agarose (0.8%, SeaPlaque; BioWhittaker Molecular Applications, Walkersville, MD), FBS (2%), and MgCl 2 (10 mM). PFU were calculated as described previously (5).…”

Drug–virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model

“…Adult male Sprague-Dawley rats (7 - 8 weeks old; Charles River Laboratories, Wilmington, MA) underwent jugular cannulation as previously described. 48 Twenty four hours later, a single dose of 5.7 × 10 11 vp/kg of either AdlacZ, Adp53 or PBS (vehicle) was administered in a volume of 500 μl followed by an equal volume of saline to ensure that virus was completely flushed from the catheter. Twenty-four hours after virus administration, 4-5 animals were sacrificed from each group to assess the effect of virus on CYP3A2.…”