It is time to start the renaissance of aptamers

ATA Scientific Pty Ltd

By Peter Davis
Thursday, 06 October, 2022

It is time to start the renaissance of aptamers

Who here has heard of an aptamer? Most people by now would have heard of RNA and are likely to have been the recipient of a strand or two thanks to COVID vaccines. Macugen was the first RNA biotherapeutic approved by the US Food and Drug Administration (FDA) in 2004, but did you know this is a pegylated RNA-modified aptamer?

This raises the question — where are they now?

“The desirable properties of aptamers such as selectivity, chemical flexibility, or cost-efficiency are faced by challenges, including a short half-life in vivo, immunogenicity, and entrapment in cellular organelles. Aptamer research is still in an early stage, and a deeper understanding of their structure, target interactions, and pharmacokinetics is necessary to catch up to the clinical market.”1

Maybe some interesting research by A/Prof Sarah Shigdar at Deakin University can help push this research back into favour. Her 2020 paper ‘Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells’2 is likely a pivotal moment for aptamers knowing the challenges to move other delivery vehicles through the BBB. Has this paper flown under the radar? Maybe, if our scientists were a little more media savvy by tagging an emotive descriptor in the titles of their papers, they would catch populous attention. Or perhaps at that time the planet seemed to be a little sidetracked by another disease! Imagine the attention this paper would have received should the media understand the EpCAM-positive tumour cells are from a breast cancer metastasis model. Furthermore, Shigdar and her co-authors say, “The prognosis for breast cancer patients diagnosed with brain metastases is poor, with survival time measured merely in months. This can largely be attributed to the limited treatment options capable of reaching the tumour as a result of the highly restrictive blood–brain barrier (BBB)”.2

Shigdar kindly explained that the drug in the DNA-based aptamer-dox conjugate appears to remain in the aptamer at physiological pH, thus avoiding off-target damage. Let’s dive in a bit deeper to find the main issues with aptamers, one being sustained circulation. This can be quite the balancing act, avoiding immediate expulsion by the kidney by making it bigger but not too big to elicit an immune response like PEG does and clearly remaining in the sweet size range to carry out the intended function.

In a recent review by Ruscio and de Franciscis, they cited, “The main obstacles to the development of RNA aptamers and other RNA therapeutics are the poor stability and rapid renal clearing rate of RNAs in circulating fluids”.3 It is encouraging that Shigdar’s research is beginning to address these.

There are two aptamers that have just gone through phase 1 trials that have shown promise. Noxxon’s A12 (Noxxon changed its name to TME Pharma) has shown success in clinical trials for glioblastoma. It is a pegylated RNA aptamer, similar to Macugen; no adverse events were reported that were due to the aptamer.4 The other aptamer is an unmodified DNA aptamer. It resulted from a partnership between AptaTargets, Aptus Biotech and academics in Spain where they just completed a dose escalating phase 1 and showed a very good safety profile — no adverse effects at all.5

It is important to make the distinction between an aptamer and other RNA molecules, given the introduction of naked RNA strands in vivo is almost certainly a sacrifice to the immune response to destroy. It boils down to structure and the mechanisms of defence inherent in the human body. RNA needs to be protected; additionally, we need to safeguard our bodies from off-target interactions of the treatment. In Figure 1, the predicted secondary structure consists of two hairpin structures connected by double-stranded regions. The site of DOX intercalation is between the GC and CG sequences in the double-stranded region of the aptamer, giving the aptamer six potential sites for intercalation.2

Figure 1: Schematic diagram of the predicted intercalation of DOX (doxorubicin) in the bifunctional aptamer. (A) TEPP aptamer. (B) TENN aptamer. Predicted sites for DOX intercalation represented by pink rectangles.2

Indulge me when I state… This is cool science!

Now we see how an aptamer is shielded from some of the body’s fortifications, but the question is, how has this been successfully achieved with drugs like Onpattro and the COVID vaccines? The answer is that they are loaded into lipid nanoparticles, the advent of which has opened the explosion of research into RNA as a treatment option for a multitude of ailments. Precision Nanosystems6 has transformed the way medical research and drug delivery is performed with a novel microfluidic platform that hands over the power of production to the research community, enabling accessibility to technologies that permit in-country manufacture of treatments, democratising medicine.

It is unlikely one modality of delivery will be the panacea, but aptamers have a role to play, the size of which is dependent on the volume of research and investment. Clearly there are a few faithful researchers across the planet doing tremendous work — thankfully! They need support akin to their colleagues in the other moiety of RNA exploration.

  1. Site accessed 31 August 2022.
  2. Site accessed 31 August 2022.
  3. “Minding the gap: Unlocking the therapeutic potential of aptamers and making up for lost time” Ruscio & de Franciscis , Molecular Therapy: Nucleic Acids Vol. 29, September 2022.
  4. Site accessed 6 September 2022.
  6. Site accessed 6 September 2022.
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