A GENE-THERAPY BASED FUNCTIONAL RESTORATION OF SALIVARY GLANDS

描述(申请人提供)：口干症是头颈癌体外放射治疗(XRT)的常见副作用，不适用于姑息治疗。因此，对于将接受XRT治疗的越来越多的人来说，这一医疗和生活质量问题仍然是一个未得到满足的医疗需求，这种疾病的发病率越来越高。最近一种治疗这种疾病的方法是基于唾液腺功能的基因治疗恢复。在这一策略中，重组腺病毒载体(Ad)通过导管内直接滴注将水通道蛋白基因转移到唾液腺上皮细胞。美国国立卫生研究院/国家牙科研究所的初步I期人类临床试验清楚地表明，这种方法可以恢复唾液流动，改善口干症状。基于这些有希望的发现，假设载体设计的进步进一步改善水通道蛋白基因传递可以促进唾液腺的功能恢复是合乎逻辑的。此外，水通道蛋白基因的长期表达的实现将扩大这种基因治疗方法治疗口干症的症状益处。在这里，我们将寻求解决干燥症基因治疗的这些载体方面的问题，以使其作为一种转化性治疗实现其对患者的全部益处价值。在第一方面，我们开发了定向修饰的Ad，它体现了显著增强的靶细胞感染性。我们推测，这些感染性增强的Ad可以改善唾液腺导管上皮细胞的水通道蛋白基因转移，从而增强功能恢复。此外，我们还开发了高容量的“无胆量”腺病毒载体(HCAd)，可以长期表达基因。我们假设，这种载体能力将使我们能够保持长期的水通道蛋白表达水平，从而允许唾液腺持续的功能重建。我们在此提出的研究将为最终开发一种新的基因治疗方法来治疗XRT引起的口干症奠定完整的基础，该方法基于将水通道蛋白输送到唾液腺导管上皮。我们还注意到，我们的方法显然可以推广到干性类固醇症(干燥综合征、慢性涎腺炎等)的不同病理生物学病因。因此，通过R21试点奖在此获得的数据可用于NCI翻译机制(NEXT等)的收购。以充分实现我们从板凳到床的转换目标。

DESCRIPTION (provided by applicant): Xerostomia is a frequent side effect of external beam radiation therapy (XRT) for head and neck cancer and is not amenable to palliative therapies. This medical and quality of life issue thus remains an unmet healthcare need for the increasing number of individuals who will receive XRT treatment for this disease of increasing incidence. A recent approach for this disorder is based upon gene therapy restoration of salivary gland function. In this strategy, a recombinant adenoviral vector (Ad) is employed to deliver the aquaporin gene to epithelial cells of the salivary glands via direct intra-ductal instillation. Preliminary phase I human clinical trials at the NIH/National Institute of Dental Research have clearly shown that this approach can restore salivary flow with an amelioration of xerostomia symptoms. Based on these promising findings, it is logical to hypothesize that vector design advancements to improve further aquaporin gene delivery could enhance functional restoration of the salivary gland. In addition, the achievement of long term expression of the aquaporin gene would extend the symptomatic benefits of this gene therapy approach for xerostomia. Herein we will seek to address these vector aspects of xerostomia gene therapy to enable its full patient benefit value to be realized as a translational therapeutic. In the first regard, we hve developed tropism modified Ad which embody dramatically enhanced target cell infectivity. We hypothesize that these infectivity enhanced Ad can accomplish improved aquaporin gene transfer for ductal epithelial cells of the salivary gland thereby augmenting functional restoratio. In addition, we have developed high capacity "gutless" adenoviral vectors (HCAd) that allow long term gene expression. We hypothesize that this vector capacity will allow us to maintain long term aquaporin expression levels to allow for sustained functional reconstitution of the salivary gland. The studies we propose herein will establish the full rationale for the ultimate development of a novel gene therapy approach for XRT-induced xerostomia based on aquaporin delivery to the ductal epithelium of the salivary gland. We also note that our approach is clearly generalizable for the diverse pathobiologies etiologic of xerostermia (Sjorgen's syndrome, chronic sialadentitis, etc.). Data acquired herein thru this R21 Pilot Award can thus be leveraged for the acquisition of NCI translational mechanisms (NExT, etc.) to fully realize our bench-to-bed translational goals.