Perspective Series

The idea of using nucleic acid molecules as therapeutic agents was conceived in the 1970s with the development of antisense strategies. Antisense compounds are single-stranded nucleic acids that, in principle, disrupt the synthesis of a targeted protein by hybridizing in a sequence-dependent manner to the mRNAs that encode it. The mechanism of inhibition by nucleic acid aptamers is fundamentally different. Aptamers are single-stranded nucleic acids that directly inhibit a protein’s function by folding into a specific three-dimensional structure that dictates high-affinity binding to the targeted protein. Through iterative in vitro selection techniques, aptamers can be generated that bind essentially any protein (or small molecule) target. A high-affinity, specific inhibitor can theoretically be made to order, provided that a small quantity of pure target is available. Because they inhibit the activity of existing proteins directly, aptamers are more similar to monoclonal antibody or small molecule drugs than to antisense compounds, and this property greatly increases the number of clinical indications that are potentially treatable by nucleic acid–based compounds. Aptamers have been generated against a wide variety of targets, a complete discussion of which is beyond the scope of this article (for review, see ref. 1). As with any molecular therapeutic approach, the inhibitor is only as effective as the target is important. Through their ability to specifically inhibit a molecule of interest, aptamers have already proven useful as reagents for target validation in a variety of disease models. The next step, therapeutic utility, will depend on the efficacy of these novel compounds in humans. In this Perspective, we will focus on the development and status of aptamers as therapeutic molecules.