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Coxsackie and adenovirus receptor binding ablation reduces adenovirus liver tropism and toxicity

 Chae-Ok Yun  ;  A-Rum Yoon  ;  Ji Young Yoo  ;  Hoguen Kim  ;  Minjung Kim  ;  Taeyong Ha  ;  Gwi Eon Kim  ;  Hyunhee Kim  ;  Joo-Hang Kim 
 HUMAN GENE THERAPY, Vol.16(2) : 248-261, 2005 
Journal Title
Issue Date
Adenoviridae/genetics ; Adenoviridae/pathogenicity* ; Adenoviridae Infections/virology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Humans ; Liver/cytology ; Liver/metabolism ; Liver/virology* ; Mice ; Mice, Inbred C57BL ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/virology* ; Protein Binding ; Receptors, Virus/genetics ; Receptors, Virus/metabolism* ; Tropism* ; Virus Replication
Human adenovirus-based vectors have emerged as a new promising vehicle for in vivo gene transfer-mediated therapy. However, the full potential of this methodology has not been fully realized because of the nonspecific tissue distribution of adenoviral vectors. Adenovirus infection is initiated by forming a complex between the fiber protein and a ubiquitously expressed host cell membrane protein, coxsackie B virus and adenovirus receptor (CAR). Therefore, ablating the adenovirus vector's ability to bind to the CAR is the first step in redirecting adenoviral tropism. To ablate CAR binding, we mutated the Bbeta sheet of the fiber knob, generating CAR-binding ablated replication-incompetent (dl-K420A-Z) and replication-competent (YKLK420A) adenoviral vectors. The in vitro transduction efficiency of dl-K420A-Z was significantly reduced in comparison to dl-LacZ carrying the wild-type fiber in CAR-positive cells but not in CAR-negative cells, suggesting that the mutation introduced in the Bbeta sheet of the fiber knob could disable the CAR-dependent transduction pathway. The in vivo transduction was also dramatically reduced in the liver and other organs for mice treated with dl-K420A-Z, compared with a cognate control vector, dl-LacZ. Concomitant with this attenuated gene transfer efficiency in vivo was a substantial reduction in the amount of general toxicity observed in the YKL-K420A-treated mice. Diminished toxicity was surmised from quantitative measurement of serum level of enzymes for liver and kidney function, hematologic chemistries, histopathology, and differences in lethality. Significant decrease in serum transaminases (alanine transferase [ALT] and aspartate transferase [AST]) was observed in mice treated with YKL-K420A. In addition, the lethality was lower in the YKLK420A- treated groups compared to the YKL-1-treated groups at all doses examined. Furthermore, the hepatopathologic analysis revealed that YKL-1 induced focal zonal necrosis and hepatocyte degeneration, while YKL-K420A induced mild spotty necrosis. In summary, this decreased vector tropism of CAR-binding ablated adenoviruses in normal tissues may increase the amount of virus available for infecting tumor cells and thus increase the antitumor efficacy with fewer unwanted side effects.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Gwi Eon(김귀언)
Kim, Minjung(김민정)
Kim, Joo Hang(김주항)
Kim, Hogeun(김호근)
Yoo, Ji Yeong(유지영)
Yoon, A Rum(윤아름)
Yun, Chae Ok(윤채옥)
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