Small and Effective

(April 13th, 2017) Aptamers are becoming increasingly popular as therapeutics and antibody alternatives. Because of their size, they could prove valuable for neurosciences, too.

Aptamers are small DNA molecules that act like antibodies. First discovered as long ago as 1990, they are now emerging as an alternative to antibodies. They are proving so useful that not only are they displacing antibodies in some cases, but are already entering into clinical trials as new therapeutics. Amazingly, despite this growing popularity, they have been almost completely neglected in the field of neuroscience.

That, however is beginning to change, and in a recent issue of the Journal of Neuroscience, Olga Wolter and Günter Mayer from the University of Bonn, Germany, make the case for a surge in interest in aptamers in brain sciences

Aptamers take advantage of the fact that short DNA or RNA molecules fold up through intra-molecular interactions to produce a unique shape. With a bit of luck, it will have just the right shape to fit into your lab's favourite molecule and, with a bit of chemical persuasion, stick to it and not let go. That means you can use aptamers for anything you use antibodies for.

So why bother, when we have been using antibodies for years to mark proteins and even interfere with protein function? There are many reasons to work with aptamers - not least because they are more predictable than antibodies (the notorious batch-to-batch variability of antibodies has ruined many a promising lab career), and they are easier to adapt to different conditions (such as high ionic strength environments).

Aptamers are made using a procedure called SELEX (Systematic Evolution of Ligands by EXponential enrichment). In short, you start off with a mix of thousands of random DNA or RNA strands. You incubate these strands with your target protein, and wash off the strands that didn't stick. Strip off the sticky ones and amplify them with RT-PCR. Repeat the process several times and you should end up with an enriched mixture.

As Wolter and Mayer point out, there are things that make aptamers appealing to neuroscience, and some labs are waking up to this. For one thing, they are a lot smaller than antibodies, making it much more realistic to load a patch pipette with them to insert them into a cell. Another appeal is that their effects on proteins can be much more nuanced than just inhibition. For example, some labs have found they can use aptamers as allosteric modulators. Finally, aptamers are small enough to tuck neatly into binding sites, such as phosphorylation sites, without completely bogging a whole protein down.

Aptamers do have some drawbacks. They are membrane-impermeant, which means that if you want to get them inside a cell you have to use some sort of delivery system, such as nanoparticles or liposomes. However, these are also limitations of antibodies. Another problem is that SELEX only works about a third of the time, according to a paper cited by Wolter and Mayer. Having said that, considerable advances have been made in improving aptamer generation, while ingenious tricks such as adding extra chemistry to residues or using non-biological nucleotides have overcome a lot of these problems.

With aptamers entering clinical trials since 2005 and an increasing array of aptamer modifications, aptamers will almost certainly continue to attract attention as a new family of tools in neuroscience.

Steven Buckingham

Picture: Structure of the biotin RNA aptamer (yellow) complexed with biotin (Fdardel, CC-BY-SA 3.0)

Last Changes: 05.08.2017