chapter  5
26 Pages

Basic Principles of Antisense Drug Discovery

WithSusan M. Freier, Andrew T. Watt

It has been nearly 30 years since the first reports of inhibition of gene expression using an antisense oligonucleotide (ASO) [1]. Although many technological hurdles remained to be solved, the potential of antisense inhibitors for therapeutic applications was clearly apparent at that time. Antisense oligonucleotides offered specificity rarely attainable with small molecule inhibitors. Specific isoforms of proteins could be targeted, allowing direct inhibition of one part of a pathway without affecting related pathways. The approach was universal. With only partial sequence of any RNA, that RNA and its products could be inhibited. Because the mechanism is universal and the chemical structures of ASOs are so similar, lessons learned for ASOs against one molecular target transferred to ASOs for other molecular targets. The result is several ASOs currently in development for a broad range of indications (Chapters 21-28).