title: Short-fiber protein of ad40 confers enteric tropism and protection against acidic gastrointestinal conditions.
abstract: The lack of vectors for selective gene delivery to the intestine has hampered the development of gene therapy strategies for intestinal diseases. We hypothesized that chimeric adenoviruses of Ad5 (species C) displaying proteins of the naturally enteric Ad40 (species F) might hold the intestinal tropism of the species F and thus be useful for gene delivery to the intestine. As oral-fecal dissemination of enteric adenovirus must withstand the conditions encountered in the gastrointestinal tract, we studied the resistance of chimeric Ad5 carrying the short-fiber protein of Ad40 to acid milieu and proteases and found that the Ad40 short fiber confers resistance to inactivation in acidic conditions and that AdF/40S was further activated upon exposure to low pH. In contrast, the chimeric AdF/40S exhibited only a slightly higher protease resistance compared with Ad5 to proteases present in simulated gastric juice. Then, the biodistribution of different chimeric adenoviruses by oral, rectal, and intravenous routes was tested. Expression of reporter β-galactosidase was measured in extracts of 15 different organs 3 days after administration. Our results indicate that among the chimeric viruses, only intrarectally given AdF/40S infected the colon (preferentially enteroendocrine cells and macrophages) and to a lesser extent, the small intestine, whereas Ad5 infectivity was very poor in all tissues. Additional in vitro experiments showed improved infectivity of AdF/40S also in different human epithelial cell lines. Therefore, our results point at the chimeric adenovirus AdF/40S as an interesting vector for selective gene delivery to treat intestinal diseases.
authors.affiliation: Centre de Biotecnologia Animal i Teràpia Gènica (CBATEG), Departament Bioquímica i Biologia Molecular, Universitat Autònoma Barcelona, Barcelona 08193, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Carolina
authors.initials: C
authors.lastname: Romero
authors.forename: Adolfo
authors.initials: A
authors.lastname: Río
authors.forename: Marta
authors.initials: M
authors.lastname: Miralles
authors.forename: Aida
authors.initials: A
authors.lastname: Raventós
authors.forename: Laura
authors.initials: L
authors.lastname: Planells
authors.forename: Joan F
authors.initials: JF
authors.lastname: Burgueño
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Perales
authors.forename: Assumpció
authors.initials: A
authors.lastname: Bosch
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Gassull
authors.forename: Ester
authors.initials: E
authors.lastname: Fernández
authors.forename: Miguel
authors.initials: M
authors.lastname: Chillon
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D005750:Gastric Juice / Q000737:chemistry / Q000378:metabolism; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000821:virology*; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D056189:Viral Tropism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D014764:Viral Proteins; D001616:beta-Galactosidase; D010447:Peptide Hydrolases