GENE THERAPY FOR BRAIN TUMORS

恶性神经胶质瘤是人均最昂贵和最病态的肿瘤。这些肿瘤患者的预后在手术、放射治疗和药物设计方面的进步在很大程度上没有改变。我们的建议提供了一个综合的努力，以转化为临床人体试验实验室的进展，在设计疱疹病毒（HSV）载体的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，包括在过去的2.5年中发表了35篇以上的论文，进行了人类逆转录病毒“基因标记试验”，设计了三项人类治疗试验。我们的研究探索疱疹病毒的血管和迁移细胞递送系统（项目4- Breakfield）和基于疱疹的扩增子载体系统。设计研究以提供高滴度的含有酶的HSV载体和基于疱疹的扩增子载体系统。研究旨在提供高滴度的HSV载体，其含有单独和协同激活前药（包括环磷酰胺和伊立替康）的酶。在Aoutus和科学咨询会议上进行的初步毒性研究增加了两个新的科学目的：我们将在啮齿动物中使用新型放射性标记追踪载体、转基因和递送细胞的递送，我们将评价细胞毒性T淋巴细胞对新型肿瘤抗原B-gal和OVA的反应，以区别于疱疹载体。在Aoutus和人体试验中，我们将与疱疹病毒载体区分开来。在Aoutus和人体试验中，我们将检查疱疹病毒载体转导到脑中后的局部CTL应答。人类和体外药物研究将由聚合物前体药物系统的制造以及单一和多种活化药物的分析和建模提供支持。所有研究都将得到肿瘤和周围脑中基因表达和变化的组织学和免疫组织化学评价以及肿瘤分子特征的支持。我们的计划定义了一个合理和科学的手段来评估和扩大基因治疗脑肿瘤的潜力。

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.