The purpose of Applications Therapeutic of Ribozymes is to provide an overview of the utility of ribozymes to selectively inhibit the expression of RNA. The ribozyme applications appearing in this book should benefit not only those experienced in ribozymes, but also those applying this ribozyme technology for the first time. It is hoped that a better understanding of the therapeutic application ofribozymes will have a significant impact on human disease in the near future. The field ofribozyme biochemistry has come a long way since the initial observation that RNA is capable of catalysis, initially in cis during processing of larger molecules and ultimately the use of ribozymes in trans to achieve cleavage of target sequence. The fundamental observation that hammerhead (and subsequently hairpin) ribozymes could be designed to cleave a target messenger RNA, and the clarification of sequence restrictions in both the ribozyme and the target RNA, have paved the ways for the use of ribozymes as a tool to manipulate gene expression at the molecular level. This had pre- ously been a domain of antisense oligonucleotides and triplex DNA. Sub- quent studies have explored the myriad biological systems in which ribozyme-mediated inhibition of genes involved in various cellular processes may be used to uncouple important signaling pathways or to reverse the p- notypic expression of a pathologic process.

This book is a collection of preclinical and clinical reports on the appli cation of gene therapy to human disease. The focus of these studies is on cancer and cardiovascular disease. There are two fundamental technologies for delivering therapeutic genes to diseased ceHs: either viral vectors, as discussed by Dr. Bal main, or non-viral vector systems, as discussed by Dr. Felgner. The strengths and limitations of each of these delivery systems are charac terized. The use of a therapeutic gene to treat a disease has taken two general approaches. The first is to introduce anormal (i. e., wild type) gene into the patient that will restore normal gene function. Dr. Weiss man has characterized the tumor suppressor gene (pS3), and has shown that it can restore normal ceH function in cancer cells. The second ap proach is to treat the disease with antisense molecules. Abnormal gene expression can be down-regulated and selectively inhibited by anti sense molecules, which can reverse the pathologie process in cancer cells. Dr. Gewirtz has demonstrated this with anti sense genes on leuke mia, while Dr. Scanlon has applied this principle using ribozymes in human carcinomas. During this symposium, Dr. Engler described clinical studies of gene therapy using growth factors to stimulate new blood vessels in patients with cardiovascular disease. Several gene therapy strategies were used for cancer: overcoming drug resistance by Dr. Bertino, a pro-drug strategy with ganciclovir by Dr."

The purpose of Applications Therapeutic of Ribozymes is to provide an overview of the utility of ribozymes to selectively inhibit the expression of RNA. The ribozyme applications appearing in this book should benefit not only those experienced in ribozymes, but also those applying this ribozyme technology for the first time. It is hoped that a better understanding of the therapeutic application ofribozymes will have a significant impact on human disease in the near future. The field ofribozyme biochemistry has come a long way since the initial observation that RNA is capable of catalysis, initially in cis during processing of larger molecules and ultimately the use of ribozymes in trans to achieve cleavage of target sequence. The fundamental observation that hammerhead (and subsequently hairpin) ribozymes could be designed to cleave a target messenger RNA, and the clarification of sequence restrictions in both the ribozyme and the target RNA, have paved the ways for the use of ribozymes as a tool to manipulate gene expression at the molecular level. This had pre- ously been a domain of antisense oligonucleotides and triplex DNA. Sub- quent studies have explored the myriad biological systems in which ribozyme-mediated inhibition of genes involved in various cellular processes may be used to uncouple important signaling pathways or to reverse the p- notypic expression of a pathologic process.