One of the drawbacks of DNA aptamers – synthetic small molecules that show promise for detecting and treating cancer and other diseases – is they do not bind readily to their targets and are easily digested by enzymes in the body. Now, scientists have found a way to produce DNA aptamers without these disadvantages.
The team – from the Institute of Bioengineering and Nanotechnology (IBN) at Agency for Science, Technology and Research (A*STAR) in Singapore – describes how they developed and tested the improved DNA technology in the journal Scientific Reports.
IBN Executive Director Prof. Jackie Y. Ying says the team created “a DNA aptamer with strong binding ability and stability with superior efficacy,” and:
“We hope to use our DNA aptamers as the platform technology for diagnostics and new drug development.”
Aptamers are a special class of synthetic ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) molecules that are showing promise for clinical use.
These small molecules could be ideal for drug applications because they can be made for highly specific targets – such as proteins, viruses, bacteria and cells.
Once aptamers are engineered for a specific target, they bind to it and block its activity.
They are the chemical equivalent of antibodies, except, unlike the antibodies currently used in drug development, they do not cause undesirable immune responses and could be easier to mass produce at high quality.
The first aptamer-based drug – an RNA aptamer for the treatment of age-related macular degeneration (AMD) – was approved in the US in 2004, and several other aptamers are currently being evaluated in clinical trials.
However, no DNA aptamer has yet been approved for clinical use because the ones currently developed do not bind well to molecular targets and are easily digested in the bloodstream by enzymes called nucleases.
In their paper, lead author Dr. Ichiro Hirao, a principal research scientist at IBN, and colleagues describe how they overcame these two problems.
To overcome the problem of weak binding, the team added a new artificial component – called an “unnatural base” – to a standard DNA aptamer, which typically has four components.
The paper describes how the addition of a fifth unnatural base component to the DNA aptamer strengthened its binding ability by 100 times.
To prevent the aptamer from being easily digested by enzymes, the team added a small piece of DNA that they call a “mini-hairpin DNA.”
Dr. Hirao says mini-hairpin DNAs are made of small DNA fragments that form a compact, stem-loop structure, like a hairpin, and this is what makes them stable.
Typically, DNA aptamers do not last longer than an hour in blood at room temperature because they are broken down by nucleases. But the team found the addition of the mini-hairpin DNA could help DNA aptamers survive for days – making them more appealing for drug development.
In their paper, the scientists describe how their modifications improved a DNA aptamer that targets a cell-signaling protein called interferon gamma.
Lab tests showed the improved aptamer survived in human blood at 37 °C after 3 days and “sustainably inhibited the biological activity” of interferon gamma, note the authors.
Dr. Hirao says their modifications show it is possible to generate DNA aptamers with great promise for clinical use: they are potentially more effective in their action, cheaper to produce and have fewer adverse side effects than conventional methods. He concludes:
“The next step of our research is to use the aptamers to detect and deactivate target molecules and cells that cause infectious diseases, such as dengue, malaria and methicillin-resistant Staphylococcus aureus (MRSA), as well as cancer.”
In December 2015, Medical News Today learned how researchers from the University of Texas at Arlington are developing a way to detect cancer cells using electronic chips coated with RNA aptamers. The team hopes it will lead to a tabletop tool that offers doctors cheaper and faster tests for disease prediction.