title: Gene therapy of c-myc suppressor FUSE-binding protein-interacting repressor by Sendai virus delivery prevents tracheal stenosis.
abstract: Acquired tracheal stenosis remains a challenging problem for otolaryngologists. The objective of this study was to determine whether the Sendai virus (SeV)-mediated c-myc suppressor, a far upstream element (FUSE)-binding protein (FBP)-interacting repressor (FIR), modulates wound healing of the airway mucosa, and whether it prevents tracheal stenosis in an animal model of induced mucosal injury. A fusion gene-deleted, non-transmissible SeV vector encoding FIR (FIR-SeV/ΔF) was prepared. Rats with scraped airway mucosae were administered FIR-SeV/ΔF through the tracheostoma. The pathological changes in the airway mucosa and in the tracheal lumen were assessed five days after scraping. Untreated animals showed hyperplasia of the airway epithelium and a thickened submucosal layer with extensive fibrosis, angiogenesis, and collagen deposition causing lumen stenosis. By contrast, the administration of FIR-SeV/ΔF decreased the degree of tracheal stenosis (P < 0.05) and improved the survival rate (P < 0.05). Immunohistochemical staining showed that c-Myc expression was downregulated in the tracheal basal cells of the FIR-SeV/ΔF-treated animals, suggesting that c-myc was suppressed by FIR-SeV/ΔF in the regenerating airway epithelium of the injured tracheal mucosa. The airway-targeted gene therapy of the c-myc suppressor FIR, using a recombinant SeV vector, prevented tracheal stenosis in a rat model of airway mucosal injury.
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mizokami
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tomifuji
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: DNAVEC Corporation, Tsukuba, Ibaraki, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Surgery, Toho University School of Medicine, Ota-Ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Molecular Diagnosis (F8), Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics*; D029082:Sendai virus / Q000235:genetics*; D014132:Trachea / Q000378:metabolism; D014135:Tracheal Stenosis / Q000401:mortality / Q000473:pathology / Q000628:therapy*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa