Introduction

Antisense oligonucleotides are short synthetic oligonucleotides, usually between 15 and 25 bases in length designed to hybridize to RNA through Watson-Crick base pairing (Fig. 1). Upon binding to the target RNA, the oligonucleotide prevents expression of the encoded protein product in a sequence-specific manner. As the rules for Watson-Crick base pairing are well characterized (1), antisense oligonucleotides represent, in principal, a simple method for rationally designing drugs. In practice, exploitation of antisense oligonucleotides for therapies has presented a unique set of challenges, some anticipated and others unanticipated. Nevertheless, antisense oligonucleotides are showing promise as therapeutic agents broadly applicable for the treatment of human diseases. Currently, there is 1 approved antisense product in the market and at least 20 agents currently in clinical trials, several of which are in advanced stages of development (Table 1). In this chapter, we summarize the properties of antisense oligo-nucleotides in terms of their application as therapeutic agents. As expected, there is significantly more information regarding first-generation phosphorothioate oligodeoxynucleotides; this serves as a good benchmark for comparison with some of the newer modified oligonucleotides. One antisense mechanism that we do not discuss in this chapter are ribozymes, as they are covered elsewhere in this volume.

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