title: Retargeting of gene expression using endothelium specific hexon modified adenoviral vector.
abstract: Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.
authors.affiliation: Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States of America. Electronic address: skaliberov@wustl.edu.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kaliberov
authors.forename: Lyudmila N
authors.initials: LN
authors.lastname: Kaliberova
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong Lu
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Preuss
authors.forename: Justin A
authors.initials: JA
authors.lastname: Barnes
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Stockard
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D002460:Cell Line; D004727:Endothelium / Q000502:physiology / Q000821:virology*; D005260:Female; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014161:Transduction, Genetic; D056189:Viral Tropism
chemical_list: D036022:Capsid Proteins; C018315:hexon capsid protein, Adenovirus
keywords: Adenovirus; Endothelium; Hexon; Roundabout 4 promoter; Targeting