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是 手术、放射治疗和药物设计的进步没有改变。我们的 建议提供了一项综合努力，将其转化为临床人类 用于传递的病毒载体设计的实验室试验进展 将药物增强基因转移到肿瘤细胞。这些研究探索了 脑内、动脉和外周递送系统。三个项目 三个核心被联合起来作为脑瘤联盟的资源 (NABTT)为向量的系统评估提供模板 大鼠和脑内肿瘤患者的基因治疗系统 胶质母细胞瘤。对媒介传递的广泛研究在 携带9L或D-74脑瘤的啮齿类动物。载体的建立 在广泛毒性之前，使用刚性模板来判断疗效 在灵长类动物身上进行测试。根据与FDA的讨论，我们认为 协作优势我们与Somatix公司的互动(用于 GMP级载体)、所有项目的统一生物统计概览和 核心以及新英格兰灵长类动物成员的参与 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 制定科学依据进行和解释小 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能力载体 来源于逆转录病毒，单纯疱疹病毒I型(HSV)和疱疹病毒- 扩增子向量。通过关注激活的酶的表达 前药物，(更昔洛韦的HSV-胸苷激酶基因，和细胞色素 对于环磷酰胺和甲基PCNU的P450基因，我们还建立了一个模型 目的：探索原位给药方法。药物研究将由一个 药理学核心，用于活性药物的分析和建模。全 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 该计划确定了一种合理而科学的方法来评估潜力 关于脑瘤的基因治疗。

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.