Targetable Vectors for Gene Therapy

描述：(申请人摘要)既有获得性疾病，如艾滋病和 癌症，以及血友病、囊性纤维化、精神分裂症等遗传性疾病 迟缓和其他许多疾病将被证明是可以通过基因疗法进行治疗的。 这种方法既是合理的，也极有可能取得戏剧性的结果。 人类基因组计划和不同学科的许多小组的工作 正在帮助快速鉴定和克隆这样一种 接近。然而，基因疗法治疗人类疾病的前景 遗传性和获得性障碍要到 交货得到了满意的解决。因此，迫切需要安全， 高效且有针对性的载体，以允许基因的传递 在研究人类基因组的过程中发现的。在这笔赠款中，我们 记录了第一个真正可靶向的基因载体系统的产生 送货。我们今天的研究已经建立了一种生产 能够实现完全肿瘤的靶向性高滴度病毒载体 动物模型中的回归。这一系统体现了 安全、高效的转导和表达，易于工程实现 以及成功的基因治疗所必需的生产。 通过这项申请，我们寻求资金来完善系统，解决一些 这些问题不仅对我们的媒介系统，而且对 一般的细胞凋亡领域。我们还寻求开发载体和治疗方法 有很大可能帮助治疗各种不同的 疾病和紊乱。我们的具体目标是：1.发展至少三个 高度凋亡的辛德比斯病毒载体将能够靶向 不断生长的人类肿瘤细胞。2.在实验动物身上检测上述载体 建立安全性、药动学、生物分布和最优的方案 成功治疗肿瘤的给药方案。3.识别和研究 抗病/感病主效基因的作用机制 细胞凋亡。这种方法是基于观察到的哺乳动物细胞是 对辛德比斯病毒介导的细胞凋亡完全敏感，而昆虫细胞 完全抵抗。这些新颖的研究与正在进行的努力相结合 研究病毒诱导的细胞凋亡，将扩大疾病的范围 可以通过Sindbis和其他病毒载体进行接触，以及贡献 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.