アンチセンスオリゴ法の臨床応用

Abstract

Clearly the antisense oligonucleotides (ODNs) concept derives from an understanding of nucleic acid structure and function and depends on Watson-Crick hybridization. Conceptually ODNs drug effects can be rationalized by traditional receptor theory and basic concepts concerning drug action. Because it was apparent almost immediately that native phosphodiester ODNs are unsatisfactory as a drug because of rapid degradation, a variety of modifications including the methylphosphonates and the phosphorothioates were tested. The phosphorothioate ODNs (s-ODNs) have potent systemic effects in a number of animal models, and in many experiments, the antisense mechanism has been directly demonstrated as the hoped-for selectivity, but pharmacodynamically, they have relatively low affinity per nucleotide unit.For a successful outcome, the s-ODNs have to meet some criteria : (1) the s-ODNs must be stable, (2) the s-ODNs must be able to enter the target cell, (3) the s-ODNs must be retained by the target cell, (4) the s-ODNs must be able to interact with their cellular targets, (5) the s-ODNs should not interact in a non-sequence-specific manner with other macromolecules.As several clinical trials are in progress with phosphorothioates and others, we shall soon have more definitive information about activity, toxicities and value of this class of antisense drugs in human beings.