Targeted Adenoviral Gene Therapy for Malignant Glioma

描述（由申请人提供）： 高级别胶质瘤是成人中枢神经系统最常见的原发性恶性肿瘤。不幸的是，仅手术干预后的中位生存期仅为6个月，加上放射治疗可以将这一时间延长至9个月。因此，旨在开发新疗法的努力集中在专门针对肿瘤细胞和备用正常细胞的新治疗策略上。一种这样的方式，基因治疗，已显示出对脑肿瘤的药物谱的承诺。基因治疗的成功取决于有效的基因递送到靶细胞中。腺病毒形式的病毒载体为基因治疗的递送提供了一种潜在的手段。然而，一些研究已经证明脑肿瘤对腺病毒载体具有相对耐药性，这一发现随后归因于肿瘤细胞上主要腺病毒受体（科萨基腺病毒受体（CAR））的数量缺陷。该项目的主要目的是开发具有增强基于免疫的癌症治疗能力的重靶向腺病毒载体。重新靶向的焦点一直是许多实体器官肿瘤中α-v-β 3和α-v-β 5的表达。该项目旨在开发第二代腺病毒，其对α-v-β 3和α-v-β 5整合素的嗜性改变，以实现免疫调节基因的细胞特异性靶向。首席研究员Maciej S. Lesniak最近完成了神经外科的住院医师培训，目前在约翰霍普金斯医院担任神经外科助理教授。Lesniak博士的近期目标是建立一个坚实的研究背景，使他能够成为一名独立的研究人员。Lesniak博士希望有一天能将这项研究转化为临床环境和恶性脑肿瘤患者的治疗。

DESCRIPTION (provided by applicant): High grade gliomas represent the most common primary malignant tumor of the adult central nervous system. Unfortunately, the median survival after surgical intervention alone is only six months and the addition of radiotherapy can extend this time to only nine months. Consequently, efforts aimed at developing new therapies have focused on new treatment strategies that specifically target tumor cells and spare normal cells. One such modality, gene therapy, has shown promise in the spectrum of agents utilized against brain tumors. The success of gene therapy depends on efficient gene delivery into target cells. Viral vectors, in the form of adenoviruses, have provided one potential means for the delivery of gene therapy. Several studies, however, have demonstrated a relative resistance of brain tumors to adenoviral vectors, a finding that was subsequently attributed to the quantitative deficiency of the primary adenoviral receptor, the Coxsackie Adenovirus Receptor (CAR), on tumor cells. The main purpose of this project is to develop re-targeted adenoviral vectors with the capacity to enhance immune based cancer therapies. The focus of the re-targeting has been the expression of alpha-v-beta3 and alpha-v-beta5 on many solid organ tumors. This project aims to develop second generation adenoviruses with altered tropism for alpha-v-beta3 and alpha-v-beta5 integrins in order to achieve cell-specific targeting of immune-modulatory genes. The principal investigator, Dr. Maciej S. Lesniak, has recently completed his residency in neurological surgery and is currently as Assistant Professor of Neurosurgery at the Johns Hopkins Hospital. Dr. Lesniak immediate goals are to establish a solid research background that will allow him to become an independent investigator. By undertaking this project and furthering his scientific and biomedical research education, Dr. Lesniak hopes to one day translate this research to the clinical setting and the treatment of patients with malignant brain tumors.