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AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands

Gene Therapy volume 18, pages 38–42 (2011)Cite this article

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Abstract

Previously (Shan et al, 2005), we reported that adenoviral vector-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to minipig parotid glands following irradiation (IR) transiently restored salivary flow to near normal levels. This study evaluated a serotype 2, adeno-associated viral (AAV2) vector for extended correction of IR (single dose; 20 Gy)-induced, parotid salivary hypofunction in minipigs. At 16 weeks following the IR parotid salivary flow decreased by 85–90%. AAV2hAQP1 administration at week 17 transduced only duct cells and resulted in a dose-dependent increase in salivary flow to ∼35% of pre-IR levels (to ∼1 ml per 10 min) after 8 weeks (peak response). Administration of a control AAV2 vector or saline was without effect. Little change was observed in clinical chemistry and hematology values after AAV2hAQP1 delivery. Vector-treated animals generated high anti-AAV2 neutralizing antibody titers by week 4 (∼1:1600) and significant elevations in salivary (∼15%), but not serum, granulocyte macrophage colony-stimulating factor levels. Following vector administration, salivary [Na+] was dramatically increased, from ∼10 to ∼55 mM (at 4 weeks) and finally to 39 mM (8 weeks). The findings demonstrate that localized delivery of AAV2hAQP1 to IR-damaged parotid glands leads to increased fluid secretion from surviving duct cells, and may be useful in providing extended relief of salivary hypofunction in previously irradiated patients.

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Acknowledgements

This work was supported by grants from the National Basic Research Program of China (2007CB947304 and 2010CB944801), the Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the jurisdiction of Beijing Municipality (PHR20090510, 2006 ID 0301200094 and KM200510025002), National Excellent PhD Theses Award grant from Ministry of Education, China (200778) and the Intramural Research Program of the National Institute of Dental and Craniofacial Research.

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  1. R Gao and X Yan: These authors contributed equally to this study.

Authors and Affiliations

  1. Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy, Capital Medical University School of Stomatology, Beijing, PR, China

    R Gao, X Yan, B Hai, J Xu, J Zhou, C Zhang & S Wang

  2. Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD, USA

    C Zheng, C M Goldsmith, S Afione, J A Chiorini & B J Baum

  3. Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, PR, China

    S Wang

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  1. R Gao
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Correspondence to B J Baum or S Wang.

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Gao, R., Yan, X., Zheng, C. et al. AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. Gene Ther 18, 38–42 (2011). https://doi.org/10.1038/gt.2010.128

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