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Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion

Gene Therapy volume 22, pages 739–749 (2015)Cite this article

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Abstract

Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial using Adenoviral gene transfer of Aquaporin-1 (AQP1) to a single salivary gland of individuals suffering from radiation-induced xerostomia has recently been reported. Unfortunately, the limitations of the Adenoviral vector system used in this pioneering trial preclude its advancement to a Phase II trial, and we have thus undertaken to evaluate the therapeutic potential of ultrasound-assisted nonviral gene transfer (UAGT) as an alternative means of delivering AQP1 gene therapy to the salivary gland by comparing head-to-head with the canonical Adenoviral vector in a swine model. Swine irradiated unilaterally with a 10-Gy electron beam targeted at the parotid gland suffered from significant, sustained hyposalivation that was bilateral, despite irradiation being confined to the targeted gland. Unilateral AQP1 gene therapy with UAGT resulted in bilateral restoration of stimulated salivary flow at 48 h and 1 week post treatment (1.62±0.48 ml and 1.87±0.45 ml) to preinjury levels (1.34±0.14 ml) in a manner comparable to Adenoviral delivery (2.32±0.6 ml and 1.33±0.97 ml). UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model, and it is a candidate for advancement to a Phase I human clinical trial.

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Acknowledgements

These studies were supported by NIH grant #DE022973 (to MJP). The authors thank E. Day Werts, PhD for expert assistance in designing the irradiation protocol. The authors also gratefully acknowledge the assistance of Suzanne Ezzo, Tara Fraser and Ashley Wilferd with animal procedures, Carol Bain for assistance with preparation of histological specimens and Kelly Shields, PhD for assistance with statistical analyses.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Gene Therapy Program, Allegheny Health Network, Pittsburgh, PA, USA

    Z Wang, L Zourelias, C Wu & M J Passineau

  2. Department of Oral Pathology, Medicine and Radiology, University of Indiana School of Dentistry, Indianapolis, IN, USA

    P C Edwards

  3. Division of Radiation Oncology, Department of Oncology, Allegheny Health Network, Pittsburgh, PA, USA

    M Trombetta

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  1. Z Wang
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Correspondence to M J Passineau.

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Wang, Z., Zourelias, L., Wu, C. et al. Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion. Gene Ther 22, 739–749 (2015). https://doi.org/10.1038/gt.2015.36

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