A GENE-THERAPY BASED FUNCTIONAL RESTORATION OF SALIVARY GLANDS

描述（由申请人提供）：口干是头颈癌外部放射治疗（XRT）的常见副作用，不适合姑息治疗。因此，对于越来越多的接受XRT治疗的人来说，这一医疗和生活质量问题仍然是一个未满足的医疗保健需求。最近一种治疗这种疾病的方法是基于恢复唾液腺功能的基因治疗。在该策略中，采用重组腺病毒载体（Ad）通过直接导管内滴注将水通道蛋白基因传递到唾液腺上皮细胞。在美国国立卫生研究院/国家牙科研究所进行的初步I期人体临床试验清楚地表明，这种方法可以恢复唾液流动，改善口干症症状。基于这些有希望的发现，我们可以合理地假设，载体设计的进步可以进一步改善水通道蛋白基因的传递，从而促进唾液腺的功能恢复。此外，实现水通道蛋白基因的长期表达将延长这种基因治疗方法对口干症的症状益处。在这里，我们将寻求解决这些载体方面的口干症基因治疗，使其充分的患者利益价值，以实现转化治疗。在第一个方面，我们已经开发出了趋向性修饰的Ad，它显著增强了靶细胞的感染性。我们假设这些传染性增强的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，我们已经开发出高容量的“无胆”腺病毒载体（HCAd），允许长期基因表达。我们假设这种载体能力将使我们能够长期维持水通道蛋白的表达水平，从而允许唾液腺的持续功能重建。我们在此提出的研究将为最终开发一种基于水通道蛋白递送到唾液腺导管上皮的xrt诱导口干病的新型基因治疗方法奠定充分的理论基础。我们还注意到，我们的方法显然适用于干燥症（Sjorgen综合征，慢性涎腺炎等）的多种病理病因学。因此，通过R21试点奖获得的数据可以用于获取NCI转化机制（NExT等），以充分实现我们的从台到床的转化目标。

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.