Gene transfer into the liver of nonhuman primates with E1-deleted recombinant adenoviral vectors: safety of readministration.
Preclinical studies were designed to investigate the safety of recombinant adenoviruses infused into the portal vein of adult rhesus monkeys, as well as the safety and efficacy of readministration of these agents. The vectors used were recombinant adenoviruses, the E1 region of which was replaced with a marker gene expression cassette. Four 3- to 5-kg rhesus monkeys underwent portal vein cannulation, and infusion of escalating doses of recombinant first-generation vector. Serial sequential liver biopsies were performed, and necropsies were performed out to 14 months. X-Gal histochemical analysis of the liver showed evidence of dose-dependent increased gene transfer throughout the liver. Quantitative analysis of histopathology showed that portal inflammation was also present in transduced livers, and occurred in a dose-dependent manner. Severe toxicity, including mortality, was noted at the highest dose of vector. Readministration of a second vector was associated with the same degree of toxicity as the first vector, but prompted a much more vigorous neutralizing antibody response. The data suggest that intraportal administration and readministration of recombinant adenoviral E1-deleted vectors are feasible and safe. Vector administration at the highest dose (1 x 10(13) particles/kg) was associated with severe clinical and biochemical toxicity, and significant gene expression was associated with transaminitis. Readministration of vector is safe, but gene transfer is limited by the presence of neutralizing antibody.
Nunes
F A
FA
Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Furth
E E
EE
Wilson
J M
JM
Raper
S E
SE
D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics*; D000818:Animals; D005260:Female; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008253:Macaca mulatta; D008297:Male; D008854:Microscopy, Electron; D009500:Neutralization Tests; D011995:Recombination, Genetic
D017498:Adenovirus E1 Proteins