title: Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion.
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.
authors: Gene Therapy Program, Division of Cardiovascular Medicine, Department of Medicine, Allegheny Health Network, Pittsburgh, PA, USA.
authors: Z
authors: Z
authors: Wang
authors: Gene Therapy Program, Division of Cardiovascular Medicine, Department of Medicine, Allegheny Health Network, Pittsburgh, PA, USA.
authors: L
authors: L
authors: Zourelias
authors: Gene Therapy Program, Division of Cardiovascular Medicine, Department of Medicine, Allegheny Health Network, Pittsburgh, PA, USA.
authors: C
authors: C
authors: Wu
authors: Department of Oral Pathology, Medicine and Radiology, University of Indiana School of Dentistry, Indianapolis, IN, USA.
authors: P C
authors: PC
authors: Edwards
authors: Division of Radiation Oncology, Department of Oncology, Allegheny Health Network, Pittsburgh, PA, USA.
authors: M
authors: M
authors: Trombetta
authors: Gene Therapy Program, Division of Cardiovascular Medicine, Department of Medicine, Allegheny Health Network, Pittsburgh, PA, USA.
authors: M J
authors: MJ
authors: Passineau
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D010306:Parotid Gland / Q000378:metabolism* / Q000528:radiation effects; D012463:Saliva / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D014465:Ultrasonics; D014987:Xerostomia / Q000628:therapy
chemical_list: D051398:Aquaporin 1