ENGINEERED HERPES SIMPLEX VIRUS FOR TREATMENT OF GLIOMAS

这个指导临床科学家发展奖的目的 应用是为校长提供必要的培训 调查员发展成为完全独立的调查员， 中枢神经系统（CNS）疾病的分子医学。 具体而言，该申请提出了设计新颖的修改， 单纯疱疹病毒（HSV）的基因组， 为人类胶质瘤开发安全有效的治疗方法。发展 这些病毒将包括外源基因插入，以增强 这些病毒的溶瘤活性。来自HSV基因组的多个基因 他将删除，以提高这种疗法的安全性。双探头将 可以用来确定潜在的和积极的分布 在治疗动物的CNS中复制HSV。 随着病毒构建体的发展，它们的生物学行为将被 在体外和体内胶质瘤模型中进行评估。这将包括 评估复制、抗肿瘤活性和外来干扰程度。 基因表达。将在scid和 携带颅内胶质瘤的c57 BL/6小鼠，以计算 免疫应答对肿瘤消退和宿主存活的影响。组织切片 将进行检查，以评估胶质瘤根除、神经毒力、残留 感染性病毒和免疫反应。有前途的结构将是 在HSV敏感的灵长类动物Aotus身上进行了神经毒力测试。 指导本培训计划的导师来自国际 单纯疱疹病毒学和神经胶质瘤生物学的专家。该计划是 由神经外科部完全认可，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，他1）开发了新的治疗模型， 基于分子医学的神经系统疾病和2）桥梁基础 科学和临床医学，将这种疗法引入临床 使用.因此，培训方案的一个组成部分将针对 发展临床试验设计和管理方面的专业知识。 候选人的直接目标是参加一个有组织的计划 这将提供必要的培训，成为一个完全独立的 研究人员在这一领域，同时研究一种新的治疗脑瘤。

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.