Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion.
Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion.
复制标题
DOI：
10.1038/gt.2015.36
复制
发表时间：
2015-09
期刊：
影响因子：
5.1
通讯作者：
Passineau MJ
中科院分区：
文献类型：
--
作者：
Wang Z;Zourelias L;Wu C;Edwards PC;Trombetta M;Passineau MJ
口干症是用于治疗头颈癌的电离辐射的常见副作用。最近报道了一项突破性的I期人类临床试验，使用腺病毒基因转移水通道蛋白-1(AQP1)到放射性口干症患者的单个唾液腺。不幸的是，在这项开创性试验中使用的腺病毒载体系统的局限性阻碍了它进入第二阶段试验，因此我们承诺通过在猪模型中进行头对头比较来评估超声辅助非病毒基因转移(UAGT)作为将AQP1基因治疗输送到唾液腺的替代方法的治疗潜力。用10GY电子束单侧照射腮腺的猪出现了明显的、持续的双侧肝细胞减退，尽管照射仅限于目标腺体。应用uAGT单侧AQP1基因治疗后48小时和一周后双侧唾液流量(1.62+/−0.48ml，1.87+/−0.45ml)恢复到损伤前水平(1.34+/−0.14ml)，与腺病毒注射(2.32+/−0.6ml，1.33+/−0.97ml)相当。UAGT可以取代腺病毒载体作为一种在受辐射的猪模型中传递AQP1基因治疗的方法，并有望进入I期人类临床试验。
Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial utilizing 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 utilized 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 non-viral 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 10Gy 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 hours and one week post-treatment (1.62+/−0.48ml, 1.87+/−0.45ml) to pre-injury levels (1.34+/−0.14ml) in a manner comparable to Adenoviral delivery (2.32+/−0.6ml, 1.33+/−0.97ml). UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model and is a candidate for advancement to a Phase I human clinical trial.