Therapeutic Aptamers: Evolving to Find their Clinical Niche

Abstract

Background: The discovery that short oligonucleotides, termed aptamers, can fold into three-dimensional structures that allow them to selectively bind and inhibit the activity of pathogenic proteins is now over 25 years old. The invention of the SELEX methodology heralded in an era in which such nucleic acid-based ligands could be generated against a wide variety of therapeutic targets.

Results: A large number of aptamers have now been identified by combinatorial chemistry methods in the laboratory and moreover, an increasing number have been discovered in nature. The affinities and activities of such aptamers have often been compared to that of antibodies, yet only a few of these agents have made it into clinical studies compared to a large and increasing number of therapeutic antibodies. One therapeutic aptamer targeting VEGF has made it to market, while 3 others have advanced as far as phase III clinical trials.

Conclusion: In this manuscript, we hope the reader appreciates that the success of aptamers becoming a class of drugs is less about nucleic acid biochemistry and more about target validation and overall drug chemistry.

Keywords: Aptamer; DNA; RNA; clinical trial; ligonucleotides; therapeutic.

Fig. (1).

A: HIV evolution and use of an RNA aptamer as a decoy. A: HIV evolved an RNA aptamer termed Trans-Activator Response (TAR) element to control its gene expression and replication. The viral trans-activator of transcription (tat) protein binds to TAR at the 5’ end of all viral RNAs and together with cellular factors activates viral gene expression and replication. B: Inhibition of HIV replication by the first described therapeutic aptamer. TAR decoy RNA aptamers bind the tat protein, preventing them from binding the viral TAR sequence, thereby inhibiting tat-mediated activation of HIV gene expression and replication [4, 14].

Fig. (2).

In Vitro Evolution of Aptamers via SELEX. Systematic Evolution of Ligands by EXponential enrichment (SELEX) is an iterative process that exposes a vast randomized library of RNA/DNA molecules of different structures to a target protein, partitions the RNA/DNA molecules that bind to the target protein from those that do not and amplifies those RNA/DNA molecules by RT-PCR [1].

Fig. (3).

Treating Age-Related Macular Degeneration (AMD) with an aptamer. A: Macugen or VEGF antibodies target Vascular Endothelial Growth Factor (VEGF) that induces neovascularization and vision loss in AMD. B: Aptamer or antibody-based VEGF inhibitors are injected into the vitreous space to bind VEGF in the eye, prevent it from binding to its target receptor and thereby inhibit neovascularization, effectively treating AMD.

Fig. (4).

Aptamer-mediated anticoagulation during percutaneous coronary intervention and antidote-mediated control of factor IXa aptamer function. Utilizing Watson-Crick base-pairing rules, an antidote oligonucleotide (RB007) can be designed to interact with a portion of the factor IXa aptamer (RB006). Upon binding and unwinding the aptamer, the antidote converts the aptamer’s structure from a functional one to an inactive conformation thereby reversing the aptamer’s ability to inhibit factor IXa activity.