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DNA aptamers: from mainstream to next-generation technologies

DNA day on April 25th, celebrates major scientific achievements concerning DNA, in particular the completion of the Human Genome Project in 2003 and the discovery of DNA’s double helix in 1953.

At Aptamer Group we work with both DNA and RNA aptamer libraries, selected according to the unique needs of each project. To celebrate DNA day we are recognising the contribution that DNA aptamers have made to life science development and breakthroughs that are on the horizon.

DNA aptamers are often more robust in assay environments and are cheaper to manufacture than their RNA counterparts. As such, DNA aptamers are often used as research reagents and affinity tools within diagnostics.

DNA is often thought of as a carrier of genetic information, like a huge blueprint at the centre of each cell, but it is in fact a highly flexible molecule that when present as short single-stranded sequences can form specific 3D shapes. Each shape is determined by the sequence and allows DNA aptamers to interact with their target protein, small molecule, glycan or lipid, as required.

Though RNA aptamers were the first to be discovered in 1990, DNA aptamers have resulted in some highly innovative breakthroughs that are used daily by scientists across the globe and are spurring exciting new technologies that could drive new breakthroughs in life science.

Taking the heat out of hot-starts with DNA aptamers

Taq DNA polymerase used in PCR reactions can add bases to ssDNA in a non-template-dependent manner. At the high temperatures used during PCR thermal cycling, this activity is reduced, and annealing becomes more stringent. Yet, at lower temperatures, including room temperature, this activity can impact the reaction specificity, leading to erroneous results. Preventing the low-temperature activity and retaining the reaction specificity is crucial to the experiment.

‘Hot-start’ PCR offered a way to overcome the specificity issues. Approaches include excluding the Taq DNA polymerase enzyme and spiking it into the mixture once thermal cycling begins at high temperatures or using antibodies specific to Taq that could block the enzyme’s activity at room temperature. In the first approach, process issues include the labor-intensive requirements of opening all the tubes during the reaction and adding small volumes of reagents, risking contamination. Antibodies are still used in ‘hot start’ reactions, but NEB, the life science reagent supplier now offers a best in class alternative, that is based on DNA aptamers.

In their product, NEB use a SOMAmer, a specific type of aptamer from SomaLogic that includes specific nucleobase modification to improve the inhibition profile and reduce unintended side effects. Just as the antibody-Taq inhibitory solution worked, the Taq aptamer used by NEB inhibits Taq polymerase at room temperature. This DNA aptamer solution has proven to yield highly specific PCR reactions with additional advantages over the antibody-Taq inhibitor:

  • The aptamer inhibition/activation process is fully reversible, preventing any further Taq activity at the end of thermal cycling.
  • The aptamer inhibition is released at lower temperatures (~45°C) than the antibody (94°C), removing the high temperature activation step and enabling faster protocols.

DNA aptamers build COVID-19 responses

At the start of the COVID-19 pandemic in 2020, Aptamer Group developed DNA aptamers specific to SARS-CoV-2. Specific aptamers to the viral spike protein and nucleocapsid protein were generated in just 17 days.

These SARS-CoV-2 specific DNA aptamers have been integrated into DeepVerge’s MicrotoxPD platform, enabling real time monitoring and detection of SARS-CoV-2 in wastewater systems to fg/mL levels. Aptamer Group was selected as the preferred affinity ligand supplier for MicrotoxPD following performance evaluation of the SARS-CoV-2 Optimers in parallel with alternative SARS-CoV-2 ligands from different suppliers. The Optimer-enabled MicrotoxPD diagnostic platform has been installed at six sites around the UK as part of the government’s Environmental Monitoring for Health Protection (EMHP) programme, with more installations expected over the coming months.

Work with the Chief Scientist Office Scotland Covid-19 Rapid Response project, used these DNA aptamers to examine low-cost aptamer-based detection of SARS-CoV-2 on biosensor platforms, showing the ability to accurately diagnose COVID-19 infections in clinical samples.

Better disease management with wearable aptamer biosensors

Wearable biosensors offer a new paradigm in disease management. The use of specific DNA aptamers in these biosensors could enable remote monitoring of drug dosing, increase understanding of metabolic changes or allow biomarker concentrations to be tracked in real-time for faster, more accurate responses. A number of companies and research teams are working with the potential for wearable biosensors. These can consist of microneedle arrays that offer a non-invasive or minimally invasive assessment. A small biosensor patch is placed under the skin in a completely pain-free manner. The microneedles penetrate the interstitial compartment allowing real-time monitoring of the biomarker of interest.

It was thought that the susceptibility of DNA aptamers to nucleases would inhibit their use on these platforms, as they cannot be as easily modified as RNA aptamers for nuclease protection. However, recent research has shown that the lifespan of state-of-the-art electrochemical aptamer biosensors past ~12 hours is driven by the loss of monolayer elements from the electrode surface (both blocking reagents and aptamers) rather than nuclease degradation of the DNA aptamers on these platforms.

DNA aptamer therapeutics offer novel immune modulation approaches

A DNA aptamer to Toll-like receptor 4 (ApTOLL) is showing excellent results in ongoing clinical trials for the prevention of the inflammatory cascade. ApTOLL is being applied in phase II clinical trials as a neuroprotective drug for acute ischemic stroke and myocardial infarction by targeting inflammation in the acute phase. It is also in phase I clinical trials to modulate the inflammatory cascade in COVID-19 patients. ApTOLL binds to and inhibits TLR4, a receptor located on the surface of immune cells responsible for initiating the inflammatory cascade. By blocking this response ApTOLL is able to modulate the inflammatory response to prevent the development of the cytokine storm syndrome in the most severe COVID-19 cases. This DNA aptamer drug has shown excellent safety profiles, consistent with the low immunogenicity of aptamers and offers a novel strategy for the treatment of a variety of inflammatory diseases with specific DNA aptamers.

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