Targetable Vectors for Gene Therapy

用于基因治疗的靶向载体

• 批准号: 6512778
• 负责人: DANIEL MERUELO
• 金额: $ 27.39万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512778
• 关键词: SCID mouse; Sindbis virus; antitumor antibody; apoptosis; athymic mouse; breast neoplasms; ganciclovir; gene therapy; lung neoplasms; neoplasm /cancer therapy; nonhuman therapy evaluation; p53 gene /protein; pharmacokinetics; thymidine kinase; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) Both acquired disorders, like AIDS and cancer, as well as inherited disorders like hemophilia, cystic fibrosis, mental retardation, and many others will prove amenable to treatment by gene therapy. The approach is both rational and highly likely to achieve dramatic results. The human genome project and the work of many groups across various disciplines are helping to rapidly identify and clone the required genes for such an approach. However, the promise of gene therapy for the treatment of human inherited and acquired disorders will not be fully realized until the issue of delivery is satisfactorily resolved. Thus, there is an urgent need for safe, efficient and targetable vectors to permit the delivery of genes being discovered in the course of studying the human genome. In this grant we document the generation of the first truly targetable vector system for gene delivery. Our studies today have established a method for production of targetable high-titered virus vectors capable of achieving complete tumor regression in an animal model. This system embodies all the attributes of safety, high efficiency of transduction and expression, and ease of engineering and production that are necessary for successful gene therapy. Through this application we seek funding to perfect the system, to resolve some issues of fundamental importance not only to our vector system but also for the field of apoptosis in general. We also seek to develop vectors and therapeutic approaches that have a high probability of helping to treat a broad variety of diseases and disorders. Our specific aims are: 1. To develop at least three highly apoptotic Sindbis-virus based vectors that would be able to target growing human tumor cells. 2. To test the above vectors in experimental animal protocols to establish safety, pharmacokinetics, biodistribution, and optimal dosing schedules for successful therapy of tumors. 3. To identify and study the mechanism of action of a major gene conferring resistance/susceptibility to apoptosis. The approach is based on the observation that mammalian cells are fully susceptible to Sindbis virus mediated apoptosis, while insect cells are completely resistant. These novel studies, in combination with ongoing efforts to investigate viral-induced apoptosis, will expand the range of diseases that can be approached with Sindbis and other viral vectors, as well as contribute important new knowledge to the field of apoptosis.

描述：（申请人的摘要）两种都获得的疾病，例如艾滋病和 癌症以及遗传性疾病，例如血友病，囊性纤维化，精神 迟钝，许多其他人将通过基因疗法进行治疗。 该方法既是理性的，又有可能取得巨大的结果。 人类基因组项目和各个学科的许多群体的工作 正在帮助快速识别和克隆此类所需的基因 方法。但是，基因治疗对人类治疗的承诺 直到问题 交付是令人满意的。因此，迫切需要安全， 有效且可靶向的向量允许基因的传递 在研究人类基因组的过程中发现。在这笔赠款中，我们 记录第一个真正可定位的基因矢量系统的生成 送货。我们今天的研究已经建立了一种生产方法 能够实现完整肿瘤的可靶向高静态病毒载体 动物模型中的回归。该系统体现了所有属性 安全性，高效率和表达效率以及工程的易用性 和成功基因疗法所必需的生产。 通过此应用程序，我们寻求资金来完善系统，解决一些 根本重要性的问题不仅对我们的向量系统，而且对 总体上凋亡领域。我们还寻求开发向量和治疗性 具有很高可能有助于治疗各种各样的大量可能性的方法 疾病和疾病。我们的具体目的是：1。至少开发三个 高度凋亡的基于sindbis-Virus的向量能够靶向 生长人类肿瘤细胞。 2。在实验动物中测试上述向量 建立安全性，药代动力学，生物分布和最佳的协议 成功治疗肿瘤的剂量时间表。 3。识别和研究 主要基因赋予抗药性/敏感性的作用机理 凋亡。该方法基于这样的观察，即哺乳动物细胞是 完全容易受到辛德比斯病毒介导的凋亡的影响，而昆虫细胞是 完全抗性。这些新颖的研究，结合了持续的努力 为了研究病毒引起的凋亡，将扩大疾病范围 可以与信德氏症和其他病毒矢量接触，并贡献 凋亡领域的重要新知识。