ENGINEERED HERPES SIMPLEX VIRUS FOR TREATMENT OF GLIOMAS

这一指导临床科学家发展奖的目的 申请的目的是为校长提供必要的培训 调查员将发展成为一名完全独立的调查员 治疗中枢神经系统疾病的分子医学。 具体地说，该应用程序建议设计新的修改 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脑胶质瘤治疗方法。最新进展 这些病毒中将包括外源基因插入以增强 这些病毒的溶瘤活性。单纯疱疹病毒基因组中的多个基因 他是否会删除以提高这种疗法的安全性。双探头将 用来确定潜伏期和活跃期的分布 在治疗动物的中枢神经系统复制HSV。 随着病毒结构的发展，它们的生物学行为将是 在体外和体内胶质瘤模型中进行评估。这将包括 复制、抗肿瘤活性和外源基因表达程度的评估 基因表达。体内评估将在SCID和SCID进行 C57BL/6小鼠移植脑胶质瘤的疗效计算 免疫反应对肿瘤消退和宿主存活的影响。组织切片 将进行检查以评估胶质瘤的根除、神经毒力、残留 传染性病毒和免疫反应。到那时，有希望的构造将是 对HSV敏感的灵长类动物Aotus进行了神经毒力测试。 指导这项培训计划的导师是国际化的。 单纯疱疹病毒学和胶质瘤生物学方面的专家。该计划是 完全得到神经外科的支持，它将提供所有 必要的资源。候选人的职业目标是成为一名 临床医生-科学家，两人都开发了治疗糖尿病的新模式 基于分子医学和2)桥梁基础的神经疾病 科学和临床医学--将这类疗法引入临床 使用。因此，培训方案的组成部分将旨在 发展临床试验设计和管理方面的专业知识。 候选人的直接目标是参加一个有组织的计划 这将为成为一个完全独立的人提供必要的培训 在研究脑瘤的一种新疗法时，他是这一领域的研究人员。

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.