Advances in Understanding the Pharmacological Properties of Antisense Oligonucleotides

Abstract

A rapid progress in the field of antisense technology and in exploiting it for therapeutic purposes has become intense. This chapter provides a summary of progress, to assess the status of the technology, to place the technology in the pharmacological context in which it is best understood, and the interpretation of experiments. The ultimate biological effect of an oligonucleotide should be influenced by the local concentration of the oligonucleotide at the target RNA, the concentration of the RNA, the rates of synthesis and degradation of the RNA, the type of terminating mechanism, and the rates of the events that result in termination of the activity of the RNA. Binding of oligonucleotides to specific sequences may inhibit the interaction of the RNA with proteins, other nucleic acids, or other factors required for essential steps in the intermediary metabolism of the RNA or its utilization by the cell. RNA molecules regulate their own metabolism. A number of structural features of RNA are known to influence stability, various processing events, subcellular distribution, and transport. Phosphorothioate oligonucleotides bind to proteins. The interactions with proteins can be divided into nonspecific, sequence-specific, and structure-specific binding events, each of which may have different characteristics and effects. To study the pharmacokinetics of phosphorothioate oligonucleotides, a variety of labeling techniques have been used. In addition to local and regional effects of antisense oligonucleotides, a growing number of well-controlled studies have demonstrated systemic effects of phosphorothioate oligodeoxynucleotides that have a therapeutic index that supports their evaluation for a number of therapeutic indications. As several clinical trials are in progress with phosphorothioates and others should be initiated shortly, more definitive information must be available about the activities, toxicities, and value of this class of antisense drugs in human beings.