Tumor-specific gene vectors for imaging and therapy of metastatic disease

描述（由申请人提供）：分子遗传成像和基因治疗有望彻底改变人类疾病的管理，但目前效率低下，因为现有的基因载体不适合临床使用。因此，我们研究计划的长期目标是通过设计安全有效的双功能基因治疗来促进这些治疗播散性癌症的模式的发展。作为实现这一目标的重要一步，本研究的目标是通过开发满足肿瘤特异性转导要求的新型病毒载体，探索实质性改善治疗和成像报告基因在肿瘤内靶向表达的可能性。我们假设这一目标可以通过合理修饰猴腺病毒（Ad） Pan7的自然趋向性来实现，其独特的生物学特性使其成为人类遗传干预的首选载体原型。这一假设将通过实现这一特定目标来验证：探索通过使用六邻体修饰的Pan7载体将有效的靶向特异性基因传递到播散性肿瘤的可行性。实现这一目标的实验策略是模拟人类Ad5型（Ad5）体内肝脏组织高效转导的自然机制，其中包括锚定在病毒六邻体蛋白上的许多受体结合配体。为了实现成像和治疗基因的高效和靶向性传递和表达，Pan7病毒粒子的主要蛋白质成分，六邻体，将被基因修饰以携带特定于人类癌症分子标记的配体。我们将利用载体编码的报告基因表达促进的无创光学成像技术，在转移性癌症动物模型中测试所提出载体的特异性和有效性，并与目前使用的载体进行比较。通过研制双功能基因制剂，能够定位和选择性地转导血管输送中的播散性肿瘤转移，该项目将改善播散性恶性疾病的诊断和治疗，这仍然是癌症相关死亡的主要原因。此外，拟议的基因传递策略预计将适用于广泛疾病的分子遗传成像和治疗，因此将对人类健康管理产生重大影响。这项工作的成功将为基因医学领域的发展做出重要贡献，因为它将为该领域提供急需的基因传递手段，将为设计此类药物建立新的策略，从而促进和加速这些药物进一步向临床应用的发展。

DESCRIPTION (provided by applicant): Molecular-genetic imaging and gene therapy that promise to revolutionize the management of human disease are currently inefficient because available gene vectors are suboptimal for clinical use. Therefore, the long-term objective of our research program is to facilitate the development of these modalities for disseminated cancers through the design of safe and efficient dual-function gene theranostics. As an important step toward this objective, the goal of this proposed research is to explore the possibility of substantial improvement of targeted intratumoral expression of therapeutic and imaging reporter genes by developing novel viral vectors that meet the requirements of tumor-specific transduction. We hypothesize that this goal can be accomplished through rational modification of the natural tropism of simian adenovirus (Ad) Pan7, whose unique biology makes it a preferred vector prototype for genetic interventions in humans. This hypothesis will be tested by accomplishing this Specific Aim: Explore the feasibility of efficient target-specific gene delivery to disseminated tumors through the use of hexon-modified Pan7 vectors. The experimental strategy to achieve this aim is to mimic the natural mechanism of the highly efficient transduction of liver tissue in vivo described for the human Ad type 5 (Ad5), which involves numerous receptor-binding ligands anchored to the viral hexon protein. To achieve highly efficient and target-specific delivery and expression of imaging and therapeutic genes, the main protein component of the Pan7 virion, the hexon, will be genetically modified to carry ligands specific for a molecular marker of human cancers. The specificity and efficacy of the proposed vectors will be tested and compared with those of the currently used vectors in an animal model of metastatic cancer using noninvasive optical imaging facilitated by the vector-encoded reporter gene expression. By yielding dual-function gene agents that will be able to locate and selectively transduce disseminated tumor metastases on vascular delivery, this project will improve diagnosis and treatment of disseminated malignant disease, which remains the major cause of cancer-related deaths. Furthermore, the proposed gene delivery strategy is expected to be suitable for molecular-genetic imaging and therapy of a broad range of diseases and will thus have a major impact on the management of human health. The success of this proposed work will be an important contribution to the developing field of gene medicine because it will provide the field with much-needed means of gene delivery, will establish a new strategy for designing such agents, and will thus facilitate and accelerate further development of these agents toward clinical applications. PUBLIC HEALTH RELEVANCE: The proposed study has direct relevance to public health because it will yield an efficient and safe vector platform for molecular-genetic imaging and the treatment of malignant disease. Successful completion of this research will enable efficient diagnosis and therapy of metastatic cancer, thus leading to saved and prolonged human life in the subpopulation of patients with highest risk.