By Bertrand Beauté

Steve Pascolo knows messenger RNA well. Long before 2020, long before the pandemic and long before the molecule became the most talked-about in the world, the University Hospital Zurich researcher was already working on the therapeutic potential of messenger ribonucleic acids (mRNA). In an interview with Swissquote Magazine, Pascolo explains how in the span of over 20 years, this molecule went from being abandoned by academic research to being a vaccine solution that could lead to a therapeutic revolution.

The first two approved vaccines for SARS-CoV-2 are mRNA vaccines. Does that surprise you?

No. The technology has been ready for a long time. But the coronavirus epidemic really sped things up. It created global demand and generated financing that confirmed the potential of mRNA. For the small community of researchers who have been studying it for a long time, this does not come as a surprise. It just confirms what we’ve been saying for 20 years: in a pandemic, this technology allows us to create a vaccine in a very short amount of time. It’s not a coincidence that the first two approved vaccines (from BioNTech and Moderna) use mRNA. It’s because this technology is the best tool we have.

Why did it take so long to emerge?

In the early days of my research, back in 1998, no one cared about mRNA. No one believed in it! We received no public funding and, without money, we couldn’t continue our research. Now, everyone is changing their tune and saying that this technology is amazing. But it’s not new, it wasn’t pulled out of a hat. We’ve been working in the shadows for 20 years.

Why was there such a lack of interest from the scientific community?

Unlike DNA, which is very stable, mRNA quickly degrades in the human body. For this reason, there was a bias against RNA. For a long time, most researchers believed that the molecule was too fragile and that it would be destroyed by the body before it could have any therapeutic or vaccinal effect. So they preferred to work on the potential of DNA instead. In my opinion, the fact that RNA degrades quickly has always been an advantage. I think that it is more secure, precisely due to the fact that it is biodegradable. That reduces the risk of complications. That said, in the vaccines currently on the market, the biotech companies had to encapsulate the mRNA in lipid nanoparticles in order to protect it and transport it into cells.

Will we start to see other mRNA vaccines?

We will likely see some older prophylactic vaccines be replaced with mRNA versions, because they are safer and much easier to produce. New vaccine products will be developed to fight viruses that we don’t have solutions for yet, such as cytomegalovirus or Zika. Clinical mRNA vaccine studies are already underway.

What other illnesses could be treated with RNA?

In theory, there could be an mRNA solution for any medical condition. The potential of this technology seems infinite. For genetic diseases such as cystic fibrosis and Duchenne muscular dystrophy, mRNA could be used to create a therapeutic protein. It could also be used to treat Alzheimer’s and Parkinson’s disease. The German company Ethris, for example, is developing an mRNA nasal spray that can restore lung function to patients with respiratory illnesses. Moderna is particularly focused on cardiac pathologies; an mRNA injection into a patient’s heart could produce proteins that repair blood vessels. And of course, there are high hopes for mRNA in the oncology field, with the development of individualised cancer-fighting vaccines.

How does that work?

Doctors take a biopsy of part of the tumour and then sequence the genome. They then produce mRNA molecules that are coded for the identified mutations. This creates a vaccine unique to the patient and results in an immune response that is targeted to the tumour. The goal is both therapeutic (tumour regression) and prophylactic (avoiding relapses after an operation). The European MERIT project – in which I am participating with BioNTech – is also conducting clinical trials with breast cancer patients.

So far, cancer vaccines have not been very effective...

Cancer cells, as well as AIDS cells, are able to escape and hide in the body because they can mutate many times. So a vaccine created from one specific tumour protein isn’t going to work. You need a big immune response. In oncology, mRNA vaccines will be able to target not just a single protein, as in the case of coronavirus, but five to 15 proteins, and possibly even more. This type of vaccine is expected to be approved by 2023.

This is not the first time that people have used the word "revolution" when a new technology emerges. At the time, gene therapy provoked a similar response...

With gene therapy, everyone was calling it a revolution, even though the technology had never yielded results. But mRNA has proven results, as evidenced by the coronavirus. The revolution happened before people even knew about it.

Which companies are best positioned to benefit from mRNA?

CureVac, BioNTech and Moderna are all doing very good work, but I think that BioNTech, with whom I collaborate, has more guarantees because its portfolio of molecules in development is more diversified. CureVac, which was created in 2000 and is the industry pioneer, has always focused on mRNA vaccines. Moderna, which was created in 2010, originally targeted mRNA-based gene therapies and only started working on vaccines in 2014. Finally, BioNTech (founded in 2008) takes a horizontal approach, and is focused on cancer treatments in a broad sense. Besides mRNA technology, it is also developing other approaches, such as cellular therapy and immunotherapy.

STEVE PASCOLO: AN MRNA PIONEER

After a PhD at the Pasteur Institute in Paris, Steve Pascolo joined the University of Tübingen in Germany in 1998. Along with several colleagues, he founded German biotech firm CureVac in 2000, where he held the role of Chief Scientific Officer (CSO). From 2003 to 2006, CureVac and the University of Tübingen clinic led the first clinical trials of mRNA‑based cancer vaccines.

In 2006, Pascolo left CureVac and joined University Hospital Zurich, where he created the "therapeutic messenger RNA" platform in 2017. As part of the European MERIT programme, he collaborates with German company BioNTech to conduct clinical trials for breast cancer patients. He is also the founder and CEO of the start‑ups Miescher Pharma and spRNA.