VECTORS FOR SUSTAINED EXPRESSION OF GENES IN THE LIVER

描述：(摘自申请者的摘要)基因疗法有望成为 获得性和遗传性疾病的治疗最多取得独一无二的进展 病理学的基本层面。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，因为 肝脏在许多先天代谢错误和后天疾病中起作用。其中之一 基因治疗中的问题领域是转基因在 肝脏中的高水平。该项目将使用创新的方法来 制定监管要素，以实现高水平和稳定的外国 肝脏中的基因表达。这些监管要素可以包括 转录元件，如启动子、增强子和基因座控制 区域，但也包括其他元素，如内含子、5‘和3’非翻译区 和聚腺苷酸化(PolyA)加成信号。这些元素应该直接 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，以便能够 有效地选择这样的监管要素。该系统还将 通过以下方式启用对指示外源DNA持久性的序列的选择 染色体整合或染色体外维持。在第二阶段 研究表明，体内选择系统将应用于开发 启动子能使外源基因在植物体内高效稳定地表达 肝脏。这些促进剂将用于第三阶段的内部开发 用于基因治疗的非病毒载体，如血友病A (第八因子)在Mirus内，并许可用于其他基因治疗、生物技术 和制药公司在他们的非病毒和病毒载体中使用。 临床上可行的基因表达系统的开发应该具有 巨大的商业价值，因为它将在基因中发挥关键作用 治疗(估计到2000年将是一个数十亿美元的市场)。 建议的商业应用：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