A GENE-THERAPY BASED FUNCTIONAL RESTORATION OF SALIVARY GLANDS

描述（由申请人提供）：口干症是头颈部癌症体外放射治疗（XRT）的常见副作用，不适合姑息治疗。因此，对于越来越多的人来说，这种医疗和生活质量问题仍然是一个未满足的医疗保健需求，他们将接受XRT治疗这种发病率不断增加的疾病。这种疾病的最新方法是基于唾液腺功能的基因治疗恢复。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递送至唾液腺的上皮细胞。在NIH/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，改善口干症状。基于这些有希望的发现，这是合乎逻辑的假设，载体设计的进步，以改善进一步的水通道蛋白基因传递可以增强功能恢复的唾液腺。此外，水通道蛋白基因的长期表达的实现将扩展该基因治疗方法对口干症的症状益处。在此，我们将寻求解决这些载体方面的口干症基因治疗，使其充分的患者受益价值，实现作为一个翻译治疗。在第一个方面，我们已经开发了向性修饰的Ad，其体现了显著增强的靶细胞感染性。我们假设这些感染性增强的Ad可以实现对唾液腺导管上皮细胞的水通道蛋白基因转移，从而增强功能性表达。此外，我们已经开发了高容量的“无肠”腺病毒载体（HCAd），允许长期的基因表达。我们假设，这种载体的能力将使我们能够保持长期的水通道蛋白的表达水平，使持续的功能重建的唾液腺。我们在此提出的研究将建立一个新的基因治疗方法的XRT诱导的口干症的基础上水通道蛋白递送到导管上皮的唾液腺的最终发展的充分理由。我们还注意到，我们的方法对于干燥症的不同病理生物学病因（Sjorgen综合征，慢性涎腺炎等）显然是可推广的。因此，通过R21试点奖获得的数据可以用于获得NCI翻译机制（NExT等）。以充分实现我们从实验室到临床的转化目标。 公共卫生相关性：尽管基因疗法已被应用于治疗肿瘤性疾病，但它尚未被广泛应用于癌症治疗相关并发症的治疗。我们的方法为基因转移技术在XRT诱导的病理学中的应用提供了基础。本文中这种新技术的应用将以显著的方式扩展对基因疗法如何应用于癌症及其相关发病率的理解。

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. PUBLIC HEALTH RELEVANCE: Whereas gene therapy has been applied to treat neoplastic disease, it has not been widely applied as an approach for cancer treatment-related complications. Our approach provides the basis for the application of gene transfer technology for XRT-induced pathobiology. The application of this novel technology herein will expand in a significant way the understandings of how gene therapy can be applied for cancer and its associated morbidities.