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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.

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Acknowledgements

We thank Miyoko Mitsu, Satomi Fujiwara and Tomonori Tsukahara for their technical assistance; and Dr Ryoko Saito (Tohoku University) for thoughtful advice and suggestions. This work was supported by a Jichi Medical University Graduate Student Start-up Grant for Young Investigators to FK in 2015. This study was also supported by the Research Program on HIV/AIDS and the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development.

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Correspondence to A Kume.

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Kurosaki, F., Uchibori, R., Mato, N. et al. Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract. Gene Ther 24, 290–297 (2017). https://doi.org/10.1038/gt.2017.19

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