Adenovirus-mediated gene transfer into rat livers: comparative study of retrograde intrabiliary and antegrade intraportal administration.
To examine the feasibility of liver-directed in vivo gene therapy, we administered recombinant adenoviruses carrying a reporter lacZ gene retrogradely into the common bile duct of rats, as well as antegradely into the portal vein. Transduction efficiency of the lacZ gene in the liver was estimated not only histochemically by X-gal staining, but also quantitatively by a chemiluminescent reporter gene assay. Retrograde infusion of adenoviruses into the common bile duct was shown to successfully induce transgene expression in the liver. Transduction efficiency induced by intrabiliary adenoviral administration was not significantly different from that induced by intraportal adenoviral administration. Although transgene expression induced not only by intraportal, but also by intrabiliary adenoviral administration was observed predominantly at periportal areas, a considerable number of cells expressing the transgene were detectable even in lobular and centrilobular areas. Mild infiltration of inflammatory cells into the liver and mild hyperplastic changes of hepatocytes were observed after intrabiliary and intraportal adenoviral administration. However, hepatic damage estimated pathologically was not substantial. Furthermore, although intrabiliary and intraportal adenoviral administration resulted in very mild elevation of liver-related serum biochemical parameters, apparent complications were not observed in any rats. Our results demonstrated in the present study suggest that retrograde administration of adenoviruses into the common bile duct can induce efficient transgene expression in the liver without causing severe adverse effects, supporting the feasibility of adenovirus-mediated gene transfer into the liver in clinical settings by means of endoscopic retrograde cholangiography.
Kuriyama
Shigeki
S
Third Department of Internal Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan. skuriyam@med.kagawa-u.ac.jp
Yoshiji
Hitoshi
H
Nakai
Seiji
S
Deguchi
Akihiro
A
Uchida
Naohito
N
Kimura
Yasuhiko
Y
Inoue
Hideyuki
H
Kinekawa
Fumihiko
F
Ogawa
Mutsumi
M
Nonomura
Takako
T
Masaki
Tsutomu
T
Kurokohchi
Kazutaka
K
Watanabe
Seishiro
S
D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001652:Bile Ducts; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007263:Infusions, Parenteral / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics
D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001616:beta-Galactosidase