Tumor-Specific Replicative Adenoviruses

描述(申请人提供)：有条件复制型腺病毒 (CRAD)在肿瘤中选择性地增殖，并已被广泛用于实现 肿瘤的溶解和转导。对这些复制型病毒来说很重要 实现肿瘤选择性复制，降低其毒性。我们的团队已经 复制缺陷的特异性反式互补方法的发展 腺病毒载体，基于能够复制的质粒的共同传递。 使用这些方法，我们已经实现了缺陷病毒的复制 必需的早期区域E1和E4。此外，我们还定义了小说 肿瘤特异性启动子(TSP)元件实现所需的 CRAd试剂的肿瘤选择性复制。我们的假设是改善 有条件复制载体的感染性和特异性将 提高他们的治疗效果。我们打算对一种纤维进行改性 具有与整合素结合的RGD基序的复制型腺病毒。这将是 提供一种不同于自然腺病毒的额外感染途径 受体。在本项目的第二部分，我们打算将这种光纤 用新方法进行修饰以实现肿瘤选择性复制 新的TSP元件对E4和/或E2的转录调控。

DESCRIPTION (provided by applicant): Conditionally replicative adenoviruses (CRAds) propagate selectively in tumors and have been used to achieve extensive lysis and transduction of tumors. It is important for these replicative viruses to achieve tumor-selective replication to reduce their toxicity. Our group has developed methods of specific trans-complementation of replication-defective adenoviral vectors based on co-delivery of plasmids that enable replication. Using these methods, we have achieved replication of viruses defective in essential early regions E1 and E4. In addition, we have defined novel tumor-specific promoter (tsp) elements for achieving the desired tumor-selective replication of CRAd agents. It is our hypothesis that improving the infectivity and specificity of conditionally replicative vectors will improve their therapeutic efficacy. We intend to modify the fiber of a replicative adenovirus with an RGD motif that binds to integrins. This will provide an additional infectivity pathway different from the natural adenovirus receptor. In the second part of this project, we intend to combine this fiber modification with new methods to achieve tumor-selective replication based on the transcriptional control of E4 and/or E2 with the novel tsp elements.