Targetable Vectors for Gene Therapy

描述：（申请人的摘要）获得性疾病，如艾滋病和 癌症，以及遗传性疾病，如血友病，囊性纤维化，精神 发育迟缓和许多其他疾病将证明可以通过基因疗法治疗。 这种方法既合理，又极有可能取得巨大的成果。 人类基因组计划和许多跨学科小组的工作 正在帮助快速识别和克隆此类基因所需的基因 approach.然而，基因疗法治疗人类肿瘤的前景 遗传性和获得性疾病将不会完全实现，直到问题， 交付得到圆满解决。因此，迫切需要安全、 有效的和可靶向的载体，以允许基因的递送， 是在研究人类基因组的过程中发现的。在这份协议中，我们 记录了第一个真正可靶向的基因载体系统的产生， 交付.我们今天的研究已经建立了一种生产 可实现完全肿瘤的靶向高滴度病毒载体 在动物模型中回归。该系统体现了 安全、高效的转导和表达以及易于工程化 和生产是成功的基因治疗所必需的。 通过这一应用我们寻求资金体系的完善，解决一些 这些问题不仅对我们的矢量系统至关重要， 凋亡的领域。我们还寻求开发载体和治疗药物， 这些方法很有可能帮助治疗各种各样的 疾病和失调。我们的具体目标是：1.发展至少三个 基于高度凋亡的辛德毕斯病毒的载体， 生长人类肿瘤细胞2.在实验动物中检测上述媒介 建立安全性、药代动力学、生物分布和最佳 用于成功治疗肿瘤的给药方案。3.确定和研究 主效基因的作用机制 凋亡该方法是基于观察到哺乳动物细胞 完全易受辛德毕斯病毒介导的细胞凋亡，而昆虫细胞 完全抵抗。这些新的研究，结合正在进行的努力， 研究病毒诱导的细胞凋亡，将扩大疾病的范围， 可以用辛德比斯和其他病毒载体来处理， 对细胞凋亡领域的重要新认识。

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.