Gene Therapy of c-myc Suppressor FUSE-Binding Protein-Interacting Repressor by Sendai Virus Delivery Prevents Tracheal Stenosis |
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Authors: | Daisuke Mizokami Koji Araki Nobuaki Tanaka Hiroshi Suzuki Masayuki Tomifuji Taku Yamashita Yasuji Ueda Hideaki Shimada Kazuyuki Matsushita Akihiro Shiotani |
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Institution: | 1. Department of Otolaryngology, Head & Neck Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.; 2. DNAVEC Corporation, Tsukuba, Ibaraki, Japan.; 3. Department of Surgery, Toho University School of Medicine, Ota-Ku, Tokyo, Japan.; 4. Department of Molecular Diagnosis (F8), Chiba University Graduate School of Medicine, Chiba City, Chiba, Japan.; Wayne State University, UNITED STATES, |
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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. |
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