VECTORS FOR SUSTAINED EXPRESSION OF GENES IN THE LIVER

描述：（改编自申请人摘要）基因治疗有望成为一种

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