title: Generation of a Kupffer cell-evading adenovirus for systemic and liver-directed gene transfer.
abstract: As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to escape Kupffer cell uptake as evidenced by producing no Kupffer cell death in vivo, not requiring predosing in vivo, and being phagocytosed less efficiently by macrophages in vitro compared to Ad5. When tested as a helper-dependent adenovirus (Ad) vector, Ad5/6 mediated higher luciferase and factor IX transgene expression than either helper-dependent adenoviral 5 (HD-Ad5) or HD-Ad6 vectors. These data suggest that the Ad5/6 hexon-chimera evades Kupffer cells and may have utility for systemic and liver-directed therapies.
authors.affiliation: Virology and Gene Therapy Program, Mayo Graduate School, Rochester, Minnesota, USA.
authors.forename: Reeti
authors.initials: R
authors.lastname: Khare
authors.forename: Shannon M
authors.initials: SM
authors.lastname: May
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.forename: Eric A
authors.initials: EA
authors.lastname: Weaver
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Amanda
authors.initials: A
authors.lastname: Rosewell
authors.forename: Nathan
authors.initials: N
authors.lastname: Grove
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D015850:Interleukin-6; D000410:Alanine Transaminase