title: Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract.
abstract: An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.|Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Kurosaki
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.|Division of Immuno-Gene and Cell Therapy (Takara Bio), Jichi Medical University, Shimotsuke, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Uchibori
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Mato
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sehara
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.|Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Urabe
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Support Center for Clinical Investigation, Jichi Medical University, Shimotsuke, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kume
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques / Q000592:standards*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012140:Respiratory Tract Diseases / Q000628:therapy; D014132:Trachea / Q000378:metabolism*; D019076:Transgenes
chemical_list: D000199:Actins