VECTORS FOR SUSTAINED EXPRESSION OF GENES IN THE LIVER

描述：（改编自申请人的摘要）基因治疗有望成为一种 在治疗获得性和遗传性疾病方面取得了巨大的进步， 病理学的基本水平。具体来说，基因转移的发展 方法进入肝细胞是非常有吸引力的核心作用， 肝脏在许多先天性代谢缺陷和后天性疾病中起作用。之一 基因治疗中的问题领域是转基因的持续表达， 肝脏中的高水平。该项目将采用创新的方法， 制定监管要素，使外国投资者能够获得高水平和稳定的投资。 肝脏中的基因表达。这些监管要素可包括 转录元件如启动子、增强子和基因座控制 区域，但也包括其他元件，如内含子、5'和3'非翻译区 和多聚腺苷酸化（polyA）添加信号。这些要素应直接 适用于产生改进的病毒和非病毒基因治疗载体。 在第一阶段研究中，建议开发一个系统， 有效地选择这些调节元件。该系统还将 能够选择指导外源DNA持续存在的序列， 染色体整合或染色体外维持。在II期 研究，体内选择系统将被应用于开发 启动子，其能够使外源基因在细胞中高水平且稳定地表达， 肝脏这些促进剂将在第三阶段用于 用于基因治疗应用如血友病A的非病毒载体 （因子VIII），并许可用于其他基因治疗、生物技术 和制药公司用于其非病毒和病毒载体。 临床上可行的基因表达系统的发展应该有 巨大的商业价值，考虑到它在基因工程中的关键作用， 治疗（估计到2000年将成为数十亿美元的市场）。 拟议商业应用：不可用

DESCRIPTION: (adapted from applicant's abstract) Gene therapy promises to be a singular advance in treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Specifically, the development of gene transfer methods into hepatocytes is very attractive given the central role that the liver plays in many inborn errors of metabolism and acquired disorders. One of the problem areas in gen therapy is the sustained expression of transgenes at high levels in the liver. This project will use an innovative approach to develop regulatory elements that will enable high and stable levels of foreign gene expression in the liver. These regulatory elements can include transcriptional elements such as promoters, enhancers and locus control regions, but also other elements like introns, 5' and 3' untranslated regions and polyadenylation (polyA) addition signals. These elements should be directly applicable to generate both improved viral and non-viral gene therapy vectors. In phase I studies, the development of a system is proposed that will allow for the efficient selection of such regulatory elements. This system will also enable selection for sequences that direct persistence of foreign DNA by chromosomal integration or extrachromosomal maintenance. During the phase II studies, the in vivo selection system will be applied to the development of promoters that enable high and stable levels of foreign gene expression in the liver. Such promoters will be used in phase III for the internal development of non-viral vectors for gene therapy applications such as for hemophilia A (factor VIII) within Mirus and licensed to other gene therapy, biotechnology and pharmaceutical companies for use within their non-viral and viral vectors. The development of a clinically viable gene expression system should have tremendous commercial value, given the critical role that it would play in gene therapy (estimated to be a multibillion market by the year 2000). PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE