Circular RNA is an emerging technology that experts believe holds a lot of promise for next-generation vaccines and gene therapies. Although it is still in the early stages of development, it could end up replacing mRNA in various therapeutic applications if it is eventually successful in the clinic, largely thanks to its superior durability, reduced immunogenicity, and cost-effective manufacturing.
But what exactly is circular RNA and what makes it such a promising new technology?
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What is circular RNA?
Circular RNA is a form of single-stranded, non-coding (meaning it doesn’t express proteins) RNA that – unlike linear RNA – forms a covalently closed continuous loop. This basically means that, in circular RNA, the 3’ and 5’ ends that are usually present in an RNA molecule are joined together.
Circular RNA was first discovered in humans in 1991. It was originally disregarded, as it was thought to represent errors in splicing and was considered to be of low abundance, but there is now an increased appreciation of its important function in gene regulation. Thousands of circRNAs have been found to be present in multiple organisms and their expression has been associated with developmental stages, physiological conditions, and diseases such as cancer.
Could circular RNA overcome the limitations of mRNA vaccines?
Circular RNA is such a promising prospect because scientists believe that it could be superior to mRNA, which has revolutionized vaccine technology in recent years.
Similar to mRNA, the primary use for circular RNA will likely be to make next-generation vaccines. But mRNA vaccines are expensive to manufacture, require cold-chain storage, and are difficult to transport, making their use complicated. And this is exactly where circular RNA could step in and take its place, as it will be more cost-effective to manufacture and is far more durable.
Additionally, the reason researchers find circular RNA so exciting when it comes to creating potential therapies is because of its chemical advantages. While linear RNA is chemically unstable, and it tends to get chopped off from the ends, circular RNA has no ends and is therefore naturally resistant to these processes, hanging around in the cell for longer. Ultimately, this could make more stable and longer-lasting vaccine candidates than mRNA, and it also means that less of the genetic material is required with circular RNA, which could lead to more vaccines being effective as single doses, and patients could suffer fewer adverse events since lower quantities of the active ingredient would be needed.
Another way that circular RNA could be superior to mRNA is that it also has the potential to go beyond vaccines.
Other therapeutic applications of circular RNA
Circular RNA could also hold promise for the development of gene therapies, which is what biotech company Circio is trying to accomplish with the technology, as its lead candidate is aimed at treating patients with alpha-1 antitrypsin (AAT) deficiency.
Erik Wiklund, chief executive officer (CEO) of Circio, told Clinical Trials Arena that he believes the company can make a massive improvement on adeno-associated virus (AAV)-based gene therapies. The primary issue with this type of gene therapy is that patients require very high doses. Not only does this make it costly, but it also drives toxicity.
“A gene therapy that expresses its protein via circRNA [circular RNA] instead of mRNA will be presumably more durable, and it can accumulate at a much higher concentration inside the cell,” explained Wikland in another article in Drug Discovery News (DDN). “Switching to circRNA expression could boost the protein output by tenfold compared to an AAV, which would reduce dosing and make it cheaper for patients.”
But it is worth noting that it is unlikely that circular RNA gene therapies can be developed as one-time therapies. Instead, patients would probably need multiple infusions throughout their lives, which could be seen as a potential downside to using circular RNA technology for developing gene therapies.
Companies bringing circular RNA into the clinic
As well as Circio, there are now several companies joining the circular RNA field. One of the leaders here is Orna Therapeutics, which entered into a collaboration with Merck in 2022 to advance its circular RNA technology, and recently acquired ReNAgade Therapeutics to actively solidify its leadership in the field.
All of the work on circular RNA is still preclinical, and it is yet to be seen whether the promise it holds will translate in the clinic. Nikolaus Rajewsky, who runs the circular RNA lab at the Max Delbrück Centre for Molecular Medicine in Berlin, mentioned to Clinical Trials Arena that when the time does come for circular RNA to enter the clinic, trial designs might be amended due to the individual characteristics of these types of candidates – but it is unlikely that these trials will be significantly different from traditional ones.
One of the most likely changes will be that patients will be monitored for longer to ensure safety due to the longer-acting features of circular RNA candidates. Additionally, there will likely be quite a bit of investigation into dosing levels until there is a better understanding of how efficacious they can be.
Wiklund believes that in 10 to 20 years, all RNA vaccines will be circular – so it might not be long now before the first circular RNA candidate enters clinical trials. For now, though, we will just have to wait and see how this emerging technology progresses and hope that it lives up to its potential.
New technologies related to circular RNA:
- Circular RNA Biomarkers for Heart Failure Diagnostics – Research Luxembourg
- Inhibition of Prostate Cancer with Novel Circular RNA – University of Virginia