title: CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors.
abstract: Intravenous administration of adenoviral vectors results mostly in hepatocyte transduction and subsequent hepatotoxicity. Because hepatocytes express high levels of the primary adenovirus receptor CAR, untargeting hepatocytes requires CAR-binding ablation. The amino acid residues of the viral fiber responsible for CAR-binding are known. We have constructed a mutant adenoviral vector unable to bind CAR and studied vector biodistribution and hepatotoxicity after intravenous administration. In contrast to a vector with wild-type fiber, the infectivity of the CAR-ablated vector is greatly reduced and not susceptible to inhibition with wild-type knob. Biodistribution and hepatotoxicity are, however, not affected by CAR-binding ablation. A possible explanation could be related to an increased blood persistence detected for the CAR-ablated vectors combined with their residual infectivity through other receptors.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: R
authors.initials: R
authors.lastname: Alemany
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000914:Antibodies, Viral / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015870:Gene Expression; D005822:Genetic Vectors / Q000378:metabolism* / Q000633:toxicity; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000821:virology*; D007275:Injections, Intravenous; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D011991:Receptors, Virus / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000914:Antibodies, Viral; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D008164:Luminescent Proteins; D011991:Receptors, Virus; D049452:Green Fluorescent Proteins