GENE THERAPY FOR BRAIN TUMORS

脑肿瘤的基因治疗

• 批准号: 6522351
• 负责人: FRED H HOCHBERG
• 金额: $ 209.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522351
• 关键词: gene therapy; glioma; neoplasm /cancer therapy; technology /technique development

Malignant gliomas represent the single most costly and morbid neoplasm per capita. The prognosis for patients with these tumors has been largely unchanged by advances in surgery, radiation therapy and drug design. Our proposal provides an integrated effort to translate to clinical human trials laboratory advances in the design of herpes virus (HSV) vectors for the delivery of drug-enhancing genes to tumor cells. These effects build on achievements including over 35 publications over the past 2.5 years, the conduct of a human retroviral "gene-marking trial" and the design of three human therapeutic trials Four Projects and four Cores are united , in collaboration with GMP vector facilities, as a resource for the brain-tumor Consortium (NABTT) to provide gene therapies of glioblastomas. Our studies explore vascular and migratory cell delivery systems (Project 4- Breakfield) of herpes virus and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes and herpes-based amplicon vector systems. Studies are designed to provide high titers of HSV vector containing enzymes which separately and in synergy activate pro-drugs including cyclophosphamide and irinotecan. Initial toxicity studies in Aoutus and Scientific Advisory meetings have resulted in the addition of two new scientific aims: We will track the delivery of vector, transgene and delivery cells using novel radiolabels in rodents and we will evaluate the Cytotoxic T Lymphocyte response to novel tumor antigens B-gal and OVA as distinguished from herpes vectors. In Aoutus and Human Trials we will distinguish from herpes vectors. In Aoutus and Human trials we will examine the local CTL responses that follow herpes vector transduction into brain. Human and in-vitro drug studies will be supported by for manufacture of polymeric pro-drug systems, and analysis and modeling for single and multiple activated drugs. All studies will be supported by histologic and immunohistochemical evaluations of gene expression and changes in tumor and surrounding brain, as well as the molecular characterization of tumors. Our program defines a rational and scientific means to evaluate and expand the potential of gen therapy for brain tumors.

恶性神经胶质瘤是人均成本最高、发病率最高的肿瘤。由于手术、放射治疗和药物设计的进步，这些肿瘤患者的预后基本上没有改变。我们的提案提供了一项综合努力，将疱疹病毒（HSV）载体设计的进展转化为临床人体试验实验室的进展，以将药物增强基因传递到肿瘤细胞。这些效果建立在成就的基础上，包括过去 2.5 年超过 35 篇出版物、人类逆转录病毒“基因标记试验”的进行以及三个人类治疗试验的设计四个项目和四个核心与 GMP 载体设施合作，作为脑肿瘤联盟 (NABTT) 的资源，提供胶质母细胞瘤的基因治疗。我们的研究探索了疱疹病毒的血管和迁移细胞传递系统（项目 4-Breakfield）和基于疱疹的扩增子载体系统。研究旨在提供含有酶的高滴度 HSV 载体和基于疱疹的扩增子载体系统。研究旨在提供含有酶的高滴度 HSV 载体，这些酶单独或协同激活前药，包括环磷酰胺和伊立替康。 Aoutus 和科学咨询会议上的初步毒性研究增加了两个新的科学目标：我们将使用新型放射性标记在啮齿类动物中追踪载体、转基因和传递细胞的传递，我们将评估细胞毒性 T 淋巴细胞对新型肿瘤抗原的反应B-gal 和 OVA 与疱疹载体不同。在 Aoutus 和人体试验中，我们将与疱疹媒介区分开来。在 Aoutus 和人体试验中，我们将检查疱疹载体转导到大脑后的局部 CTL 反应。人类和体外药物研究将得到聚合物前药系统的制造以及单一和多种活化药物的分析和建模的支持。所有研究都将得到基因表达和肿瘤及周围大脑变化以及肿瘤分子特征的组织学和免疫组织化学评估的支持。我们的计划定义了一种合理且科学的方法来评估和扩大基因治疗脑肿瘤的潜力。