Efficient gene delivery to pig airway epithelia and submucosal glands using helper-dependent adenoviral vectors

Huibi Cao, Tiago N. Machuca, Jonathan C. Yeung, Jing Wu, Kai Du, Cathleen Duan, Kohei Hashimoto, Virginia Linacre, Allan L. Coates, Kitty Leung, Jian Wang, Herman Yeger, Ernest Cutz, Mingyao Liu, Shaf Keshavjee, Jim Hu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF). However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR). Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.

Original languageEnglish
Article number55
Pages (from-to)e127
JournalMolecular Therapy - Nucleic Acids
Volume2
Issue numberOCT
DOIs
Publication statusPublished - 2013 Jan 1

Keywords

  • Cystic fibrosis
  • Lung gene delivery
  • Pig

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Cao, H., Machuca, T. N., Yeung, J. C., Wu, J., Du, K., Duan, C., Hashimoto, K., Linacre, V., Coates, A. L., Leung, K., Wang, J., Yeger, H., Cutz, E., Liu, M., Keshavjee, S., & Hu, J. (2013). Efficient gene delivery to pig airway epithelia and submucosal glands using helper-dependent adenoviral vectors. Molecular Therapy - Nucleic Acids, 2(OCT), e127. [55]. https://doi.org/10.1038/mtna.2013.55