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: Daisuke Mizokami, Koji Araki, Nobuaki Tanaka, Hiroshi Suzuki, Masayuki Tomifuji, Taku Yamashita, Yasuji Ueda, Hideaki Shimada, Kazuyuki Matsushita, Akihiro Shiotani
• Journal: PloS one (PLoS One) Vol. 10 Issue 1 Pg. e0116279 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25569246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-myc
• RNA Splicing Factors
• RNA-Binding Proteins
• Repressor Proteins
• poly-U binding splicing factor 60KDa

Topics

• Animals
• Disease Models, Animal
• Female
• Genetic Therapy
• Genetic Vectors (genetics, metabolism)
• Immunohistochemistry
• Kaplan-Meier Estimate
• Proto-Oncogene Proteins c-myc (genetics)
• RNA Splicing Factors
• RNA-Binding Proteins (genetics)
• Rats
• Rats, Sprague-Dawley
• Repressor Proteins (genetics)
• Sendai virus (genetics)
• Trachea (metabolism)
• Tracheal Stenosis (mortality, pathology, therapy)