Multimodal replicative lytic viruses for glimoa therapy

用于神经胶质细胞治疗的多模式复制裂解病毒

• 批准号: 6932370
• 负责人: DAWN E POST
• 金额: $ 13.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932370
• 关键词: Adenoviridae; DNA replication; angiogenesis inhibitors; antineoplastics; athymic mouse; biotechnology; biotherapeutic agent; cytolysis; disease /disorder model; gene expression; gene therapy; genetic promoter element; genetic regulation; glioma; herpes simplex virus 1; hypoxia; interleukin 4; laboratory rat; neoplasm /cancer therapy; neoplasm /cancer transplantation; neurotoxicology; nonhuman therapy evaluation; thrombospondins; tissue /cell culture; transfection /expression vector; virus replication; xenotransplantation

DESCRIPTION (provided by applicant): This proposal is designed to transition the primary investigator, Dawn Post, to an independent research scientist by developing a separate line of research related to her current project under the guidance of a mentor. Her research interests are to design and evaluate the therapeutic efficacy of novel replication competent oncolytic viruses for tumor therapy using preclinical cancer models with the goal of translating these findings to the clinical setting. In this study, we propose to generate novel Adenovirus (Ad) and Herpes-Simplex-Virus-1 (HSV) vectors whose cytolytic replication cycle is restricted to hypoxic tumor cells and that deliver the anti-tumorigenic interleukin-4 (IL-4) and thrombospondin 1 (TSP-1) genes. The therapeutic potential of these viruses for brain tumor treatment will then be examined using experimental glioma models. Hypoxia, a reduction in the partial pressure of oxygen is a hallmark of most solid tumors. We will exploit this difference between normal and tumor tissue to achieve tumor-specific targeting of viral replication and therapeutic gene expression using hypoxia/HIF-responsive promoters that we previously designed. We have already used one of these promoters to control the initiation of Ad replication thereby creating a hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad#1). IL-4 is a cytokine that induces a host immune response against the tumor and suppresses tumor angiogenesis. TSP-1 is an anti angiogenic protein that induces endothelial cell apoptosis and inhibits endothelial cell proliferation, migration, and formation into functional vessels. A trimodal gene therapy virus strategy consisting of viral mediated lysis of hypoxic cells, immunogene, and anti-angiogenic therapies has not been designed or tested to date and has great potential for eradicating tumors such as gliomas that have widespread areas of hypoxia and immunosuppressive and angiogenic activity. The hypothesis is that conditional replication of these viruses will lead to death of hypoxic tumor cells via the viral lytic cycle while expression of IL-4 and TSP-1 should further inhibit tumor growth by targeting normoxic tumor cells, the tumor microvasculature, and non-infected hypoxic tumor cells. These viruses can be used as a therapy for a broad range of tumors types that develop hypoxia or active HIF. The translation of these preclinical studies has the potential to directly benefit human health by improving the survival of cancer patients.

描述（由申请人提供）：该提案旨在通过在导师的指导下开发与她当前项目相关的单独研究系列，将主要研究者Dawn Post转换为独立的研究科学家。她的研究兴趣是使用临床前癌模型设计和评估新的复制能力肿瘤病毒对肿瘤治疗的治疗功效，目的是将这些发现转化为临床环境。在这项研究中，我们建议生成新型的腺病毒（AD）和疱疹 - 刺激性病毒-1（HSV）载体，其细胞溶解复制周期仅限于低氧肿瘤细胞，并提供抗肿瘤性的白介素金4（IL-4）（IL-4）和thlombospondins 1（therombospondin 1（Tspsp-1）（TSPSP-1）基因。然后，将使用实验性神经胶质瘤模型检查这些病毒对脑肿瘤治疗的治疗潜力。缺氧，氧气的部分压力降低是大多数实体瘤的标志。我们将利用我们先前设计的低氧/HIF反应性启动子来利用正常组织和肿瘤组织之间的这种差异，以实现病毒复制和治疗基因表达的肿瘤特异性靶向。我们已经使用了这些启动子其中一个来控制AD复制的启动，从而创建了缺氧/HIF依赖性复制性腺病毒（HYPR-AD＃1）。 IL-4是一种细胞因子，可诱导宿主免疫反应针对肿瘤并抑制肿瘤血管生成。 TSP-1是一种抗血管生成蛋白，可诱导内皮细胞凋亡，并抑制内皮细胞增殖，迁移并形成功能血管。迄今为止，尚未设计或测试一种由病毒介导的低氧细胞，免疫和抗血管源性疗法组成的三峰基因疗法病毒策略，该策略尚未被设计或测试，并且具有消除诸如具有广泛缺氧和免疫抑制和血管生成活动的胶质瘤等肿瘤的巨大潜力。假设是，这些病毒的有条件复制将通过病毒裂解周期导致低氧肿瘤细胞死亡，而IL-4和TSP-1的表达应通过靶向常氧性肿瘤细胞，肿瘤微胞膜和未感染的低氧肿瘤细胞来进一步抑制肿瘤的生长。这些病毒可以用作多种肿瘤类型的疗法，这些肿瘤类型会出现缺氧或活性HIF。这些临床前研究的翻译有可能通过改善癌症患者的存活而直接受益于人类健康。