Circular RNA was once viewed as an oddity: poorly understood and possibly even an artifact. That began to change in 2013, when work on naturally occurring circRNAs helped show that these molecules could have real biological functions. A decade later, the same properties that made circular RNA interesting to biologists – particularly its stability – are drawing attention from drug developers.
Here, Erik Wiklund, CEO of Circio and one of the early co-discoverers of human circular RNA, reflects on the field’s unlikely rise and what it could mean for the future of RNA-based medicines.
Can you start by giving us a bit of background about yourself, human circular RNA, and how that story began?
I have a long background in circular RNA. I worked as an academic 15 or 20 years ago, and I co-discovered it with Circio’s now Chief Technology Officer, Thomas Birkballe Hansen. We published some of the early work, and it was the classic situation where people didn’t really believe it: there were too many weird things and not enough evidence around it. But then slowly, it grew into a really promising therapeutic modality.
The field really exploded in 2013. Thomas published a paper in Nature showing biological functionality and numerous circular RNA copies, and I think that parked all the doubt that this was just some artifact or biologically irrelevant. People quickly saw the potential of circular RNA as a therapeutic format.
At that point, though, this was purely a biological phenomenon. People were describing how it happened in nature, but mRNA development was already well underway. And mRNA suffers from the major caveat that it is really unstable. It has a short half-life; it gets broken down. It is designed by nature to be chemically unstable because the cell wants to be able to regulate it up and down. As a therapeutic, that is a disadvantage because you want it to last longer than just a few hours. It also means it is unstable on the shelf.
It was quickly realized that circular RNA offered a nice alternative because, just by being circular, these RNAs are resistant to most degradation pathways. That naturally makes them much more durable. And so, immediately following those publications in 2013 to 2015, many labs started working on whether you could use it as a therapeutic format, and then companies began launching.
Some of these companies launched early, in 2020 or 2021, right at the time when Moderna and BioNTech were having great success with their mRNA COVID vaccines. I think the biggest splash was made by Flagship, the founders behind Moderna. They launched a company called Laronde with $500 million to develop circular RNA vaccines. They were calling it “the next Moderna,” which was pretty cool because it was based on our original discovery from 20 years ago – and now, suddenly, it was attracting that kind of funding.
Coming back to Circio, at that time we were developing cancer vaccines, which were going a bit out of fashion. We had relatively encouraging data, but the trials were small and the datasets were not definitive enough. People were becoming less interested in those modalities. We had this angle into circular RNA because I had that background, and funding was piling into circular RNA. So we made the strategic decision to park those old clinical programs and reinvent the company as a circular RNA player.
That was late 2021. I recruited my old colleague Thomas, and that’s how it all started. We parked all the programs and built this new platform based on circular RNA.
Can you take me back to the discovery itself? Was there a key breakthrough or even a eureka moment that you remember?
We were PhD students at the time, working in a lab led by a high-flying professor who had lots of wild ideas. He was very good at attracting funding, but not very involved in the details or in supervising his students. If you were someone who needed a lot of support and guidance, it was probably a terrible place to be. But if you were creative and liked experimenting and just messing around in the lab, it was perfect. There was a lot of freedom, good facilities, good funding, and you could basically do whatever you wanted.
We were operating in that environment and were actually looking for something completely different in the RNA field. We were searching for non-coding RNAs that were epigenetically regulating genes – a phenomenon already established in plants – and trying to find something similar in mammalian and human cells.
We found this gene where it looked like that might be happening, but there were also lots of weird things going on in that genetic locus. We were trying to resolve what was happening and understand it.
Then one day, Thomas realized that one reason this RNA was behaving so strangely was because it formed a circle – the RNA we thought was regulating the gene was actually circular. Obviously, that was a pretty novel discovery. We started digging into it, and it became very clear that the RNA really was circular. At that point, this had not really been described in human cells. We were also able to show how it was formed, and the mechanism the cell used to eliminate it.
We wrote up a manuscript and sent it to Science and Nature. One thing I learned from that process is that we probably made the mistake of putting too many weird things into one paper. There were so many unusual observations around this gene: it was circular, we were saying it was doing things, and then we were also saying it could get cleaved and removed. I think the sheer amount of strange biology made it difficult for reviewers to accept. It took more than a year of back-and-forth with the journals before they eventually rejected it. Had we focused only on the circular RNA aspect, we might have published it there and then.
The paper was eventually published in EMBO Journal, which is still a very solid molecular biology journal. A few years ago, we met the editor, and he told us it had become the most cited paper they had ever published – or at least it was at that point.
How did the work evolve after the initial discovery?
After that, I left academia, so I don’t take much credit beyond the original work. But Thomas then set out to systematically look for more examples of circular RNAs and work out their biological function.
At the beginning, because we had been looking for epigenetic regulation pathways, I think we were biased in how we interpreted the biology, and we couldn’t quite crack it. We understood how the RNA was formed and how it was degraded, but not what it actually did biologically. It turned out to be something completely different. The circular RNA functioned as a microRNA sponge.
Circular RNA is full of binding sites for microRNAs, which are very active in regulating gene expression inside the cell. We called it a sponge because, like Velcro, all the microRNAs stick onto the circle and are effectively incapacitated. Then, the circular RNA can get cleaved, and suddenly all the microRNAs are released at the same time, quickly triggering downstream effects. It is probably a mechanism cells use to react very rapidly to external stimuli.
These circular RNAs are highly present in the eye and central nervous system, which makes sense because those are tissues where you need fast responses. You may not have time to start expressing a gene from scratch – you need to switch quickly when something happens.
Once Thomas clearly demonstrated that biological function, the Nature paper became much more straightforward to publish. That paper came out in 2013 and now has more than 7,000 citations. Pretty much everyone writing about circular RNA references that paper.
After that, it became very easy for him to get grants, and he built a research group dedicated to circular RNA. He stayed in academia until, I was eventually able to convince him that working in industry is much better!
Had Hansen made any moves toward commercializing the technology or developing therapies based on the concept before joining Circio?
There were some efforts in that direction, but I think they were mainly trying to do things through the university technology transfer office, and those structures are simply not professional enough for this kind of work.
When you are an academic, you do science in a very different way. In academic labs, you investigate a mechanism, repeat the experiment two or three times, publish the paper, and then move on to the next thing. In industry research, you have to operate very differently. You do not really care about publications – you care about whether something actually works.
In fact, I would say the research is often much more careful in industry, because you need to understand exactly how something functions. You cannot take the risk of starting a manufacturing program and going into the clinic with a €20 million budget unless you are very sure the science holds up.
So Thomas joined us, and he brought his main postdoc from the lab as well. By then, they were among the most experienced circular RNA scientists in the world. They had figured out all the core biology, and now we could combine that with my more therapeutic and commercial perspective, including the ability to raise capital. And they provided the scientific foundation needed to actually turn these ideas into therapeutic strategies.
Interestingly, they say they can now spend much more time doing science in industry than they ever could in academia. Much of a group leader’s time in academia goes into grant writing, writing articles, group meetings, or having responsibility for things like fire escape coordination for the institute. Whereas here, I just need Thomas to come to a few investor meetings and make some nice-looking visuals. Apart from that, he and his team can focus almost entirely on science.
You mentioned that several other companies were already developing circular RNA-based therapies. How did you differentiate yourselves from the competition?
Our approach was different from that of other companies in the field. Orna Therapeutics and Orbital are two major circular RNA players that were recently acquired: BMS acquired Orbital in November 2025 for $1.5 billion, and Lilly acquired Orna earlier this year for its circular RNA platform. Those deals show the level of interest in this area.
But companies such as Orna, Orbital, and Laronde from Flagship are focused on synthetic, in vitro-transcribed circular RNA. That approach is essentially similar to what Moderna does with mRNA, but using a circular format.
We believed the advantages of circular RNA should also apply in any setting where a gene is expressed from a vector. If you could express that gene as circular RNA rather than linear RNA, you would expect longer durability and higher expression levels. At the time, that had not really been done.
Our company was originally a virus company with an adenoviral platform. The idea was to build on that platform to create viral and synthetic DNA vectors capable of carrying genetic payloads and expressing them as circular RNA instead of linear RNA. In doing so, we hoped to boost the potency of those therapeutics. It was a niche within circular RNA that, as far as we could see, almost no one else was pursuing.
From your perspective, what is the blue-sky potential of circular RNA technology?
I think everyone will eventually switch to circular RNA for applications where RNA is being used to express a therapeutic protein or antigen. There are some situations where it may not be applicable or may not be the best solution, but in the majority of therapeutic applications it is simply going to be so much better that people will have to make that transition.
The same applies to vector-based expression systems. The data increasingly suggest that this is the direction the field will move in. That’s also why you are seeing these huge acquisitions and deals. Lilly acquired Orna, BMS acquired Orbital – both at valuations around the $2 billion mark – and these were still preclinical-stage companies. They had not yet solved manufacturing, they had not treated a patient, and they still attracted those kinds of valuations. For comparison, I worked at a company called Algeta, which Bayer acquired in 2014 for around $3 billion – but that was after approval. The drug was already on the market. Now you are seeing companies acquired for two-thirds of that value before they have even entered the clinic. For me, that says a lot about where the field believes circular RNA is heading.
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