GENE THERAPY FOR BRAIN TUMORS

脑肿瘤的基因治疗

• 批准号: 2895437
• 负责人: FRED H HOCHBERG
• 金额: $ 132.77万
• 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 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895437
• 关键词: gene therapy; glioma

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 virus vectors for the delivery of drug-enhancing genes to tumor cells. These studies explore intracerebral, arterial and peripheral delivery systems. Three Projects and three Cores are united as a resource for the brain-tumor Consortium (NABTT) to provide a template for the systematic evaluations of vectors systems for gene therapy of intracerebral tumors in rats and patients with glioblastomas. Extensive studies of vector delivery are explored in rodents bearing 9L or D-74 brain tumors. The establishment of vector efficacy is judged using a rigid template prior to extensive toxicity testing in primates. Based on discussions with the FDA we view as collaborative strengths our interactions with the Somatix Corporation (for GMP-grade vectors), the uniform biostatistic overview of all Projects and Cores as well as the participation of members of the New England Primate Center for clinical, pathologic and immunopathologic monkey studies. By providing protocols for rigorous preclinical and clinical studies, we formulate a scientific basis for the conduct and interpretation of small population gene therapy trials. Sequential studies are designed to provide high titers of safe replication-competent and incompetent vectors derived from retrovirus, herpes simplex virus type I (HSV) and herpes- amplicon vectors. By focusing on expression of enzymes which activate pro-drugs, (the HSV-thymidine kinase gene for ganciclovir, and cytochrome P450 genes for cyclophosphamide and methyl PCNU), we also create a model to explore in-situ drug delivery. Drug studies will be supported by a pharmacology Core for analysis and modeling of activated drugs. All studies will supported by histologic studies of gene expression and neuropathology, as well as the molecular characterization of tumors. Our program defines a rational and scientific means to evaluate the potential of gene therapy for brain tumors.

恶性神经胶质瘤是最昂贵和最致命的肿瘤 人均。 这些肿瘤患者的预后在很大程度上是 手术、放射治疗和药物设计的进步没有改变。 我们的 该提案提供了一项综合努力，以转化为临床人类 试验实验室在病毒载体设计方面取得的进展 肿瘤细胞的药物增强基因。 这些研究探索 脑内、动脉和外周输送系统。 三个项目 三个核心联合起来作为脑肿瘤联盟的资源 (NABTT) 为载体的系统评估提供模板 大鼠和患者脑内肿瘤的基因治疗系统 胶质母细胞瘤。 对载体传递的广泛研究在 携带 9L 或 D-74 脑肿瘤的啮齿动物。 载体的建立 在广泛毒性之前使用严格的模板来判断疗效 在灵长类动物身上进行测试。 根据与 FDA 的讨论，我们认为 协作增强了我们与 Somatix Corporation 的互动（对于 GMP 级载体），所有项目的统一生物统计概述和 核心以及新英格兰灵长类动物成员的参与 猴子临床、病理学和免疫病理学研究中心。 经过 提供严格的临床前和临床研究方案，我们 为小规模的行为和解释制定科学依据 群体基因治疗试验。 序贯研究旨在 提供高滴度的安全复制能力和非复制能力载体 源自逆转录病毒、I 型单纯疱疹病毒 (HSV) 和疱疹病毒 扩增子载体。 通过关注激活酶的表达 前药（更昔洛韦的 HSV 胸苷激酶基因和细胞色素 P450基因为环磷酰胺和甲基PCNU），我们还创建了一个模型 探索原位药物输送。 药物研究将得到以下机构的支持 用于活性药物分析和建模的药理学核心。 全部 研究将得到基因表达和组织学研究的支持 神经病理学，以及肿瘤的分子特征。 我们的 计划定义了合理、科学的方法来评估潜力 脑肿瘤的基因治疗。