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Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction

Gene Therapy volume 24, pages 176–186 (2017)Cite this article

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Abstract

We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3–4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71–500% above baseline) in parotid flow 3–4.7 years after treatment, with improved symptoms for ~2–3 years. There were some changes in [Na+] and [Cl−] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.

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Acknowledgements

We are most grateful to the five responder-subjects (#19, 50, 99, 103 and 118), who gave so generously of their time and themselves for from 3 to 4.7 years. They enabled this long-term follow-up study to be conducted. In addition, we are sincerely appreciative of the Intramural Research Program of the National Institute of Dental and Craniofacial Research, which supported this study from its initial conception through its completion.

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Author notes

  1. L McCullagh: Deceased.

Authors and Affiliations

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

    I Alevizos, C Zheng, A P Cotrim, S Liu, L McCullagh, M E Billings, C M Goldsmith, M Tandon, S J Danielides, P Perez, N P Nikolov, J A Chiorini, G G Illei & B J Baum

  2. Department of Molecular and Cell Biology, Boston University, Boston, MA, USA

    E J Helmerhorst & F G Oppenheim

  3. Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA

    M A Catalán & J E Melvin

  4. Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

    S J Danielides

  5. Clinical Development, MedImmune, Gaithersburg, MD, USA

    G G Illei

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  1. I Alevizos
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Corresponding author

Correspondence to B J Baum.

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Competing interests

BJ Baum currently serves as a consultant to GSK, but was not so engaged during this study. The remaining authors declare no conflict of interest.

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Alevizos, I., Zheng, C., Cotrim, A. et al. Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther 24, 176–186 (2017). https://doi.org/10.1038/gt.2016.87

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