Ribozyme-Mediated Repair of Mutant p53 Transcripts in Breast Cancer Cells

摘要

This project explores the potential of a new and innovative approach to human gene therapy that may prove to be useful for the treatment or prevention of a range of genetic diseases including many types of cancer. We have previously demonstrated that a trans-splicing group I ribozyme can be employed to repair mutant transcripts in E. coli (Sullenger and Cech, Nature 1994) and mammalian cells (Jones et al., Nature Medicine 1996; Lan et al., Science 1998). Ribozyme-mediated repair of mutant mRNAs associated with a range of human diseases is now experimentally tractable, and we have begun to assess the therapeutic potential of this process for the repair of mutant transcripts implicated in the development and progression of breast cancer. Because mutation of the p53 gene is the most common genetic change seen m a wide variety of malignancies including breast cancer, we have initially focused on repair of mutant p53 transcripts. Toward this end, we have mapped the accessible sites for ribozyme binding on p53 RNAs, and using this information we have generated ribozymes that can react with and repair mutant p53 transcripts in breast cancer and other cell lines.