Gene therapy for barrett's esophagus: adenoviral gene transfer in different intestinal models.
Adenoviral gene therapy could potentially be used for treatment of patients with a Barrett's esophagus. In order to study the feasibility of this approach it is important to study adenoviral intestinal transduction both in vitro and in vivo. In the present study, we used differentiating Caco-2 cells, closed intestinal loops and a Barrett's esophagus rat model to test transduction of adenoviruses expressing green fluorescent protein. We observed a decreased adenoviral transduction from 18.6 to 2.3% in undifferentiated and differentiated Caco-2 cells, respectively. This could be improved by the use of the mucolytic agent N-acetylcysteine (NAC) and the polycation diethylaminoethyl-dextran (DEAE-dextran), which improved transduction in differentiated cells five- and ten-fold, respectively. Also an RGD-retargeted adenovirus showed an improved transduction in differentiated cells. In closed intestinal loops adenoviral transduction was limited and the use of NAC and DEAE-dextran or RGD targeting had little effect. The Barrett's esophagus rat model consisted of an esophagojejunostomy, which results in a Barrett's esophagus and esophageal tumors within 6 months. Adenoviral transduction in this model was limited and mainly localized in the basal layer of normal esophagus and stromal tissue of a Barrett's segment. We conclude that although the adenovirus shows promising results in vitro, the current adenoviral vectors are probably not suitable for patients with Barrett's esophagus.
Marsman
Willem A
WA
AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands. w.a.marsman@amc.uva.nl
Buskens
Christianne J
CJ
Wesseling
John G
JG
Van Lanschot
J Jan B
JJ
Bosma
Piter J
PJ
D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001471:Barrett Esophagus / Q000628:therapy*; D018938:Caco-2 Cells; D003637:DEAE-Dextran / Q000494:pharmacology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051381:Rats; D014161:Transduction, Genetic / Q000379:methods*
D049452:Green Fluorescent Proteins; D003637:DEAE-Dextran; D000111:Acetylcysteine