GENE THERAPY FOR BRAIN TUMORS

恶性胶质瘤是最昂贵和最病态的肿瘤 人均。 这些肿瘤患者的预后在很大程度上 手术、放射治疗和药物设计的进步并没有改变。 我们 提案提供了一个综合的努力，以转化为临床人类 试验在设计病毒载体方面的实验室进展 对肿瘤细胞的药物增强基因。 这些研究探讨了 脑内、动脉和外周递送系统。 三个项目 三个核心联合起来作为脑肿瘤联盟的资源 （NABTT）提供系统评估病媒的模板 用于大鼠和脑内肿瘤患者的基因治疗的系统 胶质母细胞瘤 载体递送的广泛研究在 携带9 L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刚性模板判断疗效 在灵长类动物身上做实验 根据与FDA的讨论，我们认为 合作加强了我们与Somatix公司的互动（为 GMP级载体），所有项目的统一生物统计概述， 核心以及参与成员的新英格兰灵长类动物 临床、病理学和免疫病理学猴子研究中心。 通过 为严格的临床前和临床研究提供方案，我们 制定一个科学的基础上进行和解释的小 群体基因治疗试验 序贯研究旨在 提供高滴度的安全的有复制能力的和无复制能力的载体 来源于逆转录病毒、I型单纯疱疹病毒（HSV）和疱疹病毒。 扩增子载体。 通过关注酶的表达， 前体药物（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 药理学用于活性药物分析和建模的核心。 所有 研究将得到基因表达的组织学研究的支持， 神经病理学以及肿瘤的分子表征。 我们 该计划确定了一个合理和科学的方法来评估潜力， 脑肿瘤的基因治疗。

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.