Substitution of Hexon Hypervariable Region 5 of Adenovirus Serotype 5 Abrogates Blood Factor Binding and Limits Gene Transfer to Liver

• Published in: Molecular therapy Vol. 16; no. 8; pp. 1474 - 1480
• Main Authors: Vigant, Frédéric, Descamps, Delphyne, Jullienne, Betsy, Esselin, Stéphanie, Connault, Elisabeth, Opolon, Paule, Tordjmann, Thierry, Vigne, Emmanuelle, Perricaudet, Michel, Benihoud, Karim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2008; Elsevier Limited; Cell Press
• Subjects: Adenoviridae - genetics; Adenoviruses; Alanine Transaminase - blood; Animals; Biochemistry; Biochemistry, Molecular Biology; Capsid Proteins - genetics; Carcinoma, Lewis Lung - blood; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - pathology; Cell Line, Tumor; Gene therapy; Genetic Vectors - genetics; Genomes; Heparan sulfate; Interleukin-6 - blood; Leukocyte Count; Life Sciences; Liver; Liver - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Nude; Peptides; Platelet Count; Polymerase Chain Reaction; Proteins; Toxicity; Transduction, Genetic - methods; Tumors; Vectors (Biology); France
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2008.132

Liver tropism potentially leading to massive hepatocyte transduction and hepatotoxicity still represents a major drawback to adenovirus (Ad)-based gene therapy. We previously demonstrated that substitution of the hexon hypervariable region 5 (HVR5), the most abundant capsid protein, constituted a valuable platform for efficient Ad retargeting. The use of different mouse strains revealed that HVR5 substitution also led to dramatically less adenovirus liver transduction and associated toxicity, whereas HVR5-modified Ad were still able to transduce different cell lines efficiently, including primary hepatocytes. We showed that HVR5 modification did not significantly change Ad blood clearance or liver uptake at early times. However, we were able to link the lower liver transduction to enhanced HVR5-modified Ad liver clearance and impaired use of blood factors. Most importantly, HVR5-modified vectors continued to transduce tumors in vivo as efficiently as their wild-type counterparts. Taken together, our data provide a rationale for future design of retargeted vectors with a safer profile.