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其当前项目相关的单独研究系列，将主要研究者 Dawn Post 转变为独立研究科学家。她的研究兴趣是使用临床前癌症模型设计和评估新型具有复制能力的溶瘤病毒用于肿瘤治疗的治疗效果，目的是将这些发现转化为临床环境。在这项研究中，我们建议生成新型腺病毒（Ad）和单纯疱疹病毒-1（HSV）载体，其溶细胞复制周期仅限于缺氧肿瘤细胞，并传递抗肿瘤白细胞介素-4（IL-4）和血小板反应蛋白 1 (TSP-1) 基因。然后将使用实验性神经胶质瘤模型来检查这些病毒治疗脑肿瘤的治疗潜力。缺氧（氧分压降低）是大多数实体瘤的标志。我们将利用正常组织和肿瘤组织之间的这种差异，使用我们之前设计的缺氧/HIF 响应启动子来实现病毒复制和治疗基因表达的肿瘤特异性靶向。我们已经使用这些启动子之一来控制 Ad 复制的起始，从而创建缺氧/HIF 依赖性复制腺病毒 (HYPR-Ad#1)。 IL-4 是一种细胞因子，可诱导宿主针对肿瘤的免疫反应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、迁移和形成功能性血管。由病毒介导的缺氧细胞裂解、免疫基因和抗血管生成疗法组成的三模式基因治疗病毒策略迄今为止尚未被设计或测试，并且具有根除肿瘤的巨大潜力，例如具有广泛缺氧、免疫抑制和血管生成区域的神经胶质瘤活动。假设这些病毒的条件复制将通过病毒裂解循环导致缺氧肿瘤细胞死亡，而 IL-4 和 TSP-1 的表达应通过靶向常氧肿瘤细胞、肿瘤微血管系统和非肿瘤细胞来进一步抑制肿瘤生长。感染缺氧的肿瘤细胞。这些病毒可用于治疗多种导致缺氧或活性 HIF 的肿瘤类型。这些临床前研究的转化有可能通过提高癌症患者的生存率来直接造福人类健康。