ENGINEERED HERPES SIMPLEX VIRUS FOR TREATMENT OF GLIOMAS

用于治疗神经胶质瘤的工程单纯疱疹病毒

• 批准号: 6187699
• 负责人: JAMES M MARKERT
• 金额: $ 11.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187699
• 关键词: Aotus; Herpesviridae; SCID mouse; bioengineering /biomedical engineering; biotechnology; disease /disorder model; gene expression; gene therapy; glioma; laboratory mouse; molecular cloning; neoplasm /cancer therapy; neoplastic cell; neuropathology; nonhuman therapy evaluation; recombinant virus; tissue /cell culture; transfection; transfection /expression vector; virulence; virus cytopathogenic effect; virus replication

The purpose of this Mentored Clinical Scientist Development Award application is to provide the necessary training for the principal investigator to develop into a fully independent investigator applying molecular medicine to diseases of the central nervous system (CNS). Specifically, the application proposes to engineer novel modifications into the genome of herpes simplex viruses (HSV) for the purpose of developing a safe and effective therapy for human gliomas. The development of these viruses will include foreign gene inserts to enhance the oncolytic activity of these viruses. Multiple genes from the HSV genome will he deleted to enhance the safety of this therapy. Double probes will be utilized to determine the distribution of both latent and actively replicating HSV in the CNS of treated animals. As virus constructs are developed, their biologic behavior will be evaluated in both in vitro and in vivo glioma models. This will include assessment of replication, antitumor activity, and the degree of foreign gene expression. In vivo evaluations will be conducted in both scid and c57BL/6 mice bearing intracranial gliomas to calculate the effects of immune response on tumor regression and host survival. Tissue sections will be examined to evaluate glioma eradication, neurovirulence, residual infectious virus, and immune response. Promising constructs will then be tested for neurovirulence in the HSV-sensitive simian primate, Aotus. The mentors who will direct this training proposal are international experts in herpes simplex virology and in glioma biology. The program is fully endorsed by the Division of Neurosurgery, which will provide all necessary resources. The candidate's career objective is to become a clinician-scientist who both 1) develops new models for the treatment of neurological diseases based on molecular medicine and 2) bridges basic science and clinical medicine by bringing such therapies into clinical use. An integral portion of the training program will thus be aimed at developing expertise in the design and administration of clinical trials. The candidate's immediate goals are to participate in an organized program that will provide the necessary training to become a fully independent investigator in this area while studying a novel therapy for brain tumors.

指导临床科学家发展奖的目的 申请是为校长提供必要的培训 调查员发展成为一名完全独立的调查员 分子医学治疗中枢神经系统（CNS）疾病。 具体来说，该申请建议进行新颖的修改 进入单纯疱疹病毒（HSV）的基因组，目的是 开发一种安全有效的人类神经胶质瘤治疗方法。发展历程 这些病毒将包含外源基因插入以增强 这些病毒的溶瘤活性。 HSV 基因组中的多个基因 将他删除以增强这种疗法的安全性。双探头将 用于确定潜在和主动的分布 在接受治疗的动物的中枢神经系统中复制HSV。 随着病毒构建体的发展，它们的生物学行为将发生变化 在体外和体内神经胶质瘤模型中进行评估。这将包括 复制、抗肿瘤活性和异源程度的评估 基因表达。体内评估将在 scid 和 携带颅内神经胶质瘤的 c57BL/6 小鼠计算以下因素的影响 免疫反应对肿瘤消退和宿主存活的影响。组织切片 将进行检查以评估神经胶质瘤根除、神经毒力、残留 传染性病毒和免疫反应。那么有前途的结构将是 对 HSV 敏感的猿猴灵长类动物 Aotus 进行了神经毒力测试。 指导本培训计划的导师是国际化的 单纯疱疹病毒学和神经胶质瘤生物学专家。该计划是 得到神经外科部门的完全认可，该部门将提供所有 必要的资源。候选人的职业目标是成为 临床医生兼科学家，1) 开发治疗以下疾病的新模型 基于分子医学的神经系统疾病和 2) 基础桥梁 通过将此类疗法引入临床来科学和临床医学 使用。因此，培训计划的一个组成部分将旨在 发展临床试验设计和管理方面的专业知识。 候选人的近期目标是参加有组织的计划 这将提供必要的培训以成为完全独立的人 该领域的研究人员正在研究一种脑肿瘤的新疗法。