Enhancing viral oncolysis with vasculostatin gene delivery

 描述（由申请人提供）：本提案的最终目标是利用表达Vstat 120的溶瘤HSV-1病毒（oHSV）进行神经胶质瘤治疗。Vstat 120是脑血管生成抑制剂1（BAI 1）的细胞外片段，具有强效的抗血管生成和抗肿瘤作用。在最后一个循环中，我们在不同的病毒骨架中产生了两种表达Vstat 120的溶瘤病毒。RAMBO是第一代表达Vstat 120的病毒，在类似于G207的双重减毒病毒骨架中产生，其已在患者中进行测试并发现是安全的。与具有相同骨架但缺乏Vstat 120表达的对照病毒相比，RAMBO在具有已建立的脑肿瘤的小鼠中显示出显著更好的抗肿瘤功效[5]。34.5ENVE，第二代表达Vstat 120的病毒，在巢蛋白启动子控制下转录驱动的病毒骨架中产生。34.5 ENVE在表达高巢蛋白水平的GBM模型中表现出最佳功效。鉴于34.5ENVE的抗肿瘤功效的显著改善，我们已经与NIH（NCI NeXT计划和NINDS CREATE计划）一起对其进行了转化开发。NINDS和NCI的顾问所表达的担忧是巢蛋白在一些正常细胞中表达的事实，促使我们重新考虑巢蛋白驱动的ICP 34.5表达。在这里，我们提出（目的1）调节34.5ENVE的骨架，以精确控制其在肿瘤细胞中的复制，并最大限度地减少对正常脑神经元和神经干细胞的毒性。我们将进一步（目的2）评价该病毒单独和（目的3）与蛋白酶体抑制剂联合使用的免疫学结果。在这个项目的结论，我们将有一个优化的溶瘤HSV载体，表达Vstat 120，可以追求与NIH的翻译开发。

 DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to leverage Vstat120 expressing oncolytic HSV-1 viruses (oHSV) for glioma therapy. Vstat120 is the extracellular fragment of Brain Angiogenesis Inhibitor 1 (BAI1) that has potent anti-angiogenic and anti-tumor effects. During the last cycle we created two Vstat120 expressing oncolytic viruses in different virus backbones. RAMBO, the first generation Vstat120 expressing virus, was created in a doubly attenuated virus back bone that is similar to G207, which has been tested in patients and found to be safe. RAMBO showed significantly better anti-tumor efficacy in mice with established brain tumors compared to the control virus with an identical backbone but lacking Vstat120 expression [5]. 34.5ENVE, the second generation Vstat120 expressing virus, was created in a virus backbone that is transcriptionally driven under the control of a nestin promoter. 34.5ENVE showed the best efficacy in GBM models that expressed high nestin levels. Given the significant improvement in anti-tumor efficacy of 34.5ENVE we have pursued its translational development with NIH (NCI NeXT program and NINDS CREATE program). The concern articulated by advisors at both NINDS and NCI was the fact that nestin is expressed in some normal cells, prompting us to reconsider tighter of nestin driven ICP34.5 expression. Here we propose to (Aim 1) modulate the backbone of 34.5ENVE to precisely control its replication in tumor cells and minimize toxicity to normal brain neurons and neural stem cells. We will further (Aim 2) evaluate the immunological consequences of this virus alone and (Aim 3) in conjunction with proteasome inhibition. At the conclusion of this project we will have an optimized oncolytic HSV vector that expresses Vstat120 which can be pursued for translational development with NIH.