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Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

Gene Therapy volume 14, pages 1243–1248 (2007)Cite this article

Abstract

Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.

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Acknowledgements

We gratefully acknowledge Cathleen Duan for assistance in performing β-galactosidase assays, and Dr Colin McKerlie (Hospital for Sick Children, Toronto, Canada) for assistance in histological assessment of inflammation in the mouse airways. This work was supported by Operating Grants from the Canadian Institutes of Health Research, the Canadian Cystic Fibrosis Foundation and the Foundation Fighting Blindness-Canada. J Hu is a CCFF Scholar and recipient of the CCFF Zellers Senior Scientist Award, and holds a Premier's Research Excellence Award of Ontario, Canada.

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Authors and Affiliations

  1. Physiology and Experimental Medicine Research Program, Hospital for Sick Children, Toronto, Ontario, Canada

    R Kushwah, J R Oliver, H Cao & J Hu

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    R Kushwah, J R Oliver & J Hu

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  1. R Kushwah
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  2. J R Oliver
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  3. H Cao
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  4. J Hu
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Correspondence to J Hu.

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Kushwah, R., Oliver, J., Cao, H. et al. Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways. Gene Ther 14, 1243–1248 (2007). https://doi.org/10.1038/sj.gt.3302968

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