"The Ghost Of mRNA's Future": 2025 Outlook From RNA Leaders

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Last week, Advancing RNA was pleasantly haunted by some very important “ghosts” — namely the “Ghosts of mRNA’s Past & Present,” á la Charles Dickens’ A Christmas Carol. Several RNA/LNP executives — all of whom are alive and well today — shared their perspectives on learnings from the past year in the RNA space in the first of this two-part 2025 Outlook Q&A series. 

But as the Dickens fans among us already know, there is still one pretty important “ghost” that has yet to be channeled on this “hallowed” page, and that’s the “Ghost of mRNA/RNA Innovations Yet To Come.” (Yes. That’s a thing.)

Below, I share several future-facing “visions” from the conversations I had with the following executives:

• Dominik Witzigmann, CEO & co-founder, NanoVation Therapeutics;
• Guillaume Pfefer, CEO of Sail Biomedicines;
• Benita Nagel, co-founder & CEO, & Albert Kwok, co-founder & CSO, Nuntius Therapeutics;
• Gopi Shanker, CSO, Beam Therapeutics; and
• Alexander Zehnder, CEO, CureVac

As you’ll likely note upon reading, there’s fortunately one big difference between the “Ghost of mRNA/RNA Innovations Yet To Come” and the ominous wraith confronting Dickens’ cantankerous Ebenezer Scrooge: Though the future being spelled out here for our sector is just as instructive, the challenges and opportunities facing us are certainly much more bright.

 

ARW: Funding has been top-of-mind for the entire ATMP space in the past few years. What have you observed about the funding landscape for mRNA/RNA products throughout 2024, and how are these trends informing your company’s strategies moving into 2025?

Zehnder: What is clear looking at our valuations of many companies in this space is that the platform no longer garners the same attention or investment on the financial market. Investors are prioritizing products in the clinic, with a preference for products that have been derisked and are in later-stage development. As I’ve said before, there are still many who believe that mRNA is a “one trick pony.” But as we continue to see more data released in oncology and other indications, I believe that RNA companies will encounter greater investor receptivity to the platform. At this point in time, however, we are and will continue to be rewarded predominantly for bringing drugs into the clinic and making progress.

Shanker: 2024 was a reminder of the importance of investment and continued financial support. We’ve seen the investor community move from supporting platform companies to being much more asset-driven in the past few years. This is where keeping the end in mind and choosing an indication where there is high unmet need is essential. This way, you’re not only developing your platform technology and de-risking it, you’re also able to give reassurance and confidence to investors that your asset will generate value. I’m hopeful that the current funding dynamics encourage more companies to start working together on some of the most challenging areas of development, including delivery. Afterall, both payload companies and delivery companies are striving to answer the same question: How do we turn our technology into an asset that will meet patient needs and garner investor support?

 

ARW: There are a lot of areas in which our knowledge of our RNA products needs to grow. What advancements can we make in the upcoming year to help augment our knowledge about our RNA products, and in what specific ways will these advancements benefit the RNA space as a whole?

Zehnder: As I mentioned previously, there’s a great need in our space for more clinical data, which will help de-risk RNA therapeutics and broaden the partnership landscape in the RNA space. Having worked for 20 years in Big Pharma, I know how much value larger companies place on de-risked technologies. More clinical data will likely be a key driver in bringing Big Pharma more firmly into the RNA field in the future. But we shouldn’t be overlooking the importance of partnerships with academic institutions as well. For example, earlier this year, CureVac partnered with MD Anderson Cancer Center to co-develop novel mRNA-based cancer vaccines. I’d love to see more discovery and R&D partnerships across the RNA space in the upcoming year(s).

Shanker: In the gene editing space, one of the biggest areas we need to continue to grow our knowledge is in cell biology. As I’ve emphasized before, our products are beholden to each target cell’s unique “subcellular” dynamics, which influence our product’s durability, potency and translatability. Over the past year, we’ve seen progress made in editing hematopoietic stem cells in bone marrow. These cells have always been particularly hard to edit efficiently. Ex vivo development offers more control of the process and, in turn, greater editing efficiency, but the holy grail would be to achieve the same editing efficiency when delivering an mRNA-LNP product directly to the bone marrow in vivo. Recently, we saw Editas Medicine and Tessera Therapeutics release data showing meaningful levels of editing in hematopoietic stem cells in vivo, so the field is making some progress. But it’s not just enough to know that we can edit these cells; there must be a durable effect. So, there are still questions we must answer around why these cells are more challenging to edit and which mechanisms have made current editing advancements possible.

Witzigmann: The data we saw from Intellia’s in vivo gene editing program this year are highly encouraging. At the same time, the data also shows interpersonal differences between patient responses, which we don’t yet understand. As a community, I think we should take a page from the antibody field and improve patient stratification to ensure we’re targeting the appropriate population for our trials. This would also pave the way for “N-of-1” therapies for rare indications in which each patient has individual, private mutations. There is also a lot we can learn from all the omics data — genomics, proteomics, transcriptomics. Medical professionals store so much patient data. To treat rare genetic diseases or cancer, we need to determine how we can best use this data to ensure our personalized RNA therapies meet patients’ unique needs.

 

ARW: What technological advancements will be most helpful in our efforts to learn more about our drug substances/drug products in the next few years?

Nagel: I believe that applying machine learning is already proving key to staying at the forefront of innovation — and it’s only going to become more critical. Take what we’re doing at Nuntius as an example. We’re pioneering a novel nucleic acid delivery technology that’s highly modular and programmable, giving us a large library of millions of distinct carriers to work with. The challenge is that this is a very complex system — understanding the intricate interactions between molecular features, sequences, and delivery performance is far beyond what humans can tease out. That’s where machine learning comes in. Our models help us make sense of these highly complex datasets, predicting carrier quality and performance in a way that allows us to pre-screen candidates computationally. This makes a big difference. Instead of relying on lengthy and costly trial-and-error screening processes, we’re able to move faster, significantly reduce costs and prioritize the most promising candidates. Ultimately, this accelerates the development of high-performing therapies and brings them to patients much sooner.

Pfefer: Designing RNA medicines is so complex; the design domains are vast, and, as a space, we’re used to thinking about the cargo of our drug products as separate from that of the delivery vehicle. Now, we’re starting to acknowledge the importance of integrating RNA-LNP design together – as we are doing at Sail with Endless RNA™ and our proprietary nanoparticles, programmed in tandem. However, this makes the design domain even larger. I don’t believe there’s any other way to address this complexity than to rely on artificial intelligence and machine learning. To me, machine learning is not a buzz word; it is a key piece of technology in the toolkit to accelerate, capitalize upon, and apply our learnings from one product to another, accelerating the generation of future waves of products and improving their performance each time.

Witzigmann: Firstly, I’m excited about advancements in machine learning and AI, specifically for predicting and analyzing RNA stability or optimizing antigen design. I see these technologies being most effective in the design of the RNA cargo today. When it comes to delivery systems like LNPs, I would argue that we cannot generate enough in vivo data, best in different species, to be able to rely on AI/ML for LNP design. I think we need much, much more data in vivo, to predict LNPs’ biodistribution, pharmacokinetics, interspecies differences or how LNPs interact with different cell types. A rational design approach will continue to outperform AI-based strategies in developing effective LNPs for the years to come. 

Secondly, as an industry we have aligned around analytical technologies and attributes that are “must-haves” in a development program. However, there are a lot of new characterization tools coming to the market, and over the past year, there have been an increasing number of discussions around which and how many of these new technologies should be part of standard characterization protocols. Ultimately, I think this calls attention to our ongoing need for greater alignment and standardization of the benchmarks we rely on for testing LNPs. We are starting to see some movement on this front; for example, the NRC Canada has a certified LNP reference material to improve testing reproducibility across the field. Likewise, in Europe, SINTEF is heavily working on the quality assessment of LNP-RNA systems with different orthogonal analytical techniques to help correlate certain data and quality attributes.

 

ARW: Beyond technological advancements, are there other areas of innovation that you’d like to see the RNA space explore more thoroughly in 2025?

Zehnder: The nonviral infectious disease space is fascinating, especially because there’s a huge unmet need to overcome antibiotic resistance. Seeing as mRNA can target multiple antigens in oncology, I believe mRNA is also uniquely suited to target bacterial and fungal infections. These are certainly difficult and largely unexplored targets today. But this goes back to my point that, as a space, we need to find areas in which mRNA/RNA technology is uniquely suited to tackle scientific problems in a different way, and the noninfectious disease space could be a valuable area of further exploration for our field.