GENE THERAPY OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM

中枢神经系统疾病的基因治疗

• 批准号: 6111891
• 负责人: E H OLDFIELD
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6111891
• 关键词: Retroviridae; Rodentias; autoradiography; blood brain barrier; brain neoplasms; central nervous system neoplasms; choroid plexus; drug delivery systems; gene therapy; method development; neoplasm /cancer blood supply; neoplasm /cancer relapse /recurrence; neoplasm /cancer therapy; positron emission tomography; transfection; transfection /expression vector

New approaches to transfer genetic material into tumor and normal central nervous system (CNS) tissue are being explored. The mechanisms involved in effecting antitumor activity using the suicide gene transfer approach are investigated. Normal CNS structures, tumors, normal and tumor vasculature, and choroid plexus epithelium are being targeted. New viral vectors, including adenoviruses, are being evaluated for potential therapeutic approaches. A clinical trial for treating patients with recurrent malignant brain tumors with a retroviral vector containing the gene for Herpes simplex thymidine kinase (HS Tk) and intravenous ganciclovir (GCV) was completed. The results indicate that 1) the producer-cell approach can be used successfully without toxicity in human brain tumors, 2) antitumor activity occurs in some patients, 3) limited gene transfer into tumor cells occurs with the current approach for delivery and distribution, and 4) "bystander effect" probably underlies the antitumor activity. These results highlight the need for improved methods of drug delivery and distribution in solid tumors. Therefore, we are currently investigating techniques to enhance the delivery of genetic vectors to the CNS and to CNS tumors via intracarotid infusion after selectively opening the blood-tumor barrier using a short-acting nitric oxide donor. The results indicate that this approach might be an effective and safe new way of opening the blood-brain barrier in patients with brain tumors to enhance delivery and distribution of genetic vectors. In addition, we are studying the distribution of an adenoviral vector in normal brain and tumors with convection-enhanced delivery. We are also developing methods to quantify gene delivery to the brain and to tumors. Using a radiolabeled adenoviral vector, we are studying the distribution of the viral vector in normal brain tissue and tumors using quantitative autoradiography (QAR) and modern image analysis techniques. With this approach, it might be possible to develop a method to monitor the distribution of genetic material in patients with brain tumors using positron-emission tomography (PET). Improving the efficacy of gene therapy for CNS malignancies also requires the design of novel, more effective genetic vectors. In contrast to replication-deficient viral vectors whose distribution is limited to a small diameter around the injection site, replication-competent vectors are more likely to be distributed in a larger portion of the tumor. We are currently investigating the efficacy of replication-permissive adenoviral vector carrying the TK gene which preferably replicates in p53 mutant cells in a nude rat glioma model.

将遗传物质转移到 肿瘤和正常中枢神经系统（CNS）组织正在被 探讨了影响抗肿瘤活性的机制 使用自杀基因转移方法进行研究。正常 CNS结构、肿瘤、正常和肿瘤血管系统，以及 脉络丛上皮是目标。新的病毒载体， 包括腺病毒，正在评估其潜在的 治疗方法。一项临床试验， 复发性恶性脑肿瘤的逆转录病毒载体， 单纯疱疹胸苷激酶（HS Tk）基因， 静脉注射更昔洛韦（GCV）完成。结果表明 1）生产细胞方法可以成功地使用， 在人类脑肿瘤中的毒性，2）抗肿瘤活性发生在一些 3）有限的基因转移到肿瘤细胞发生与患者， 目前的交付和分配方法，以及4）“旁观者” “效果”可能是抗肿瘤活性的基础。这些结果 强调需要改进药物输送方法， 在实体瘤中的分布。因此，我们目前 研究提高基因载体传递的技术 通过颈动脉内输注， 选择性地打开血肿瘤屏障， 一氧化氮供体结果表明，这种方法可能是 一种有效安全的打开血脑屏障的新方法 脑肿瘤患者，以提高交付和分配 基因载体此外，我们正在研究一个 腺病毒载体在正常脑和肿瘤中的表达 对流增强输送。我们还在开发方法， 量化基因向大脑和肿瘤的传递。使用 放射性标记的腺病毒载体，我们正在研究的分布 使用定量方法检测正常脑组织和肿瘤中的病毒载体 放射自显影（QAR）和现代图像分析技术。 通过这种方法，可能会开发出一种方法， 监测大脑疾病患者的遗传物质分布 正电子发射断层扫描（PET）。提高 CNS恶性肿瘤基因治疗的有效性还需要 设计新的、更有效的遗传载体。相比 复制缺陷型病毒载体，其分布仅限于 注射部位周围直径较小，可复制 矢量更可能分布在更大的部分， 肿瘤我们目前正在研究 携带TK基因的允许复制的腺病毒载体 其优选在裸鼠神经胶质瘤中的p53突变细胞中复制 模型