Top 5 mRNA/RNA Developments of 2024 (Part 1)

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

A little over a year ago, Life Science Connect launched Advancing RNA.

At the beginning of January 2024, I took the helm of Advancing RNA as its Editorial & Community Director. And, to quote Dr. Seuss: “Oh, the places [we’ve gone].”

We started the year off — as one naturally does — with a visit to “Barbieland” (a.k.a. Advanced Therapies Week Miami…). We kept the metaphors (and Hot Takes!) coming during a keynote for a BioPhorum ATMP-centric member event. We celebrated my 10-year anniversary with Life Science Connect on stage, moderating an RNA panel at the World Vaccine Congress in D.C. We had countless Aperol spritzes with ATMP market fortune-teller Charles Dickens at the AGC CDMO Summit in Milan and teamed up as a media partner with the inaugural Alliance for mRNA Medicines Ascent Conference in Boston. And, because traveling is expensive but learning is necessary, we hosted four virtual Advancing RNA Live panel discussions (which you can stream here) and published upwards of 80 columns on RNA and the biopharma universe with the help of our fabulous expert network of contributors. A seriously huge kudos to each of those contributors and my colleagues Michelle Raley and Jon O’Connell; Advancing RNA would not be what it is without you.

But Advancing RNA wasn’t the only one having a big year. mRNA has been taking Dr. Seuss’ words to heart: “[She’s] got brains in her head, feet in [her] shoes, and” — as some of the developments from the past year would indicate — “[She’s] steering herself in any direction [she] chooses.”

In the past few weeks, I’ve shared two articles outlining several RNA executives’ thoughts on advancements from 2024, as well as the challenges facing us in 2025. But why stop there? Below in the first of this two-part article, I share the first two of my five overarching observations from 2024. The encoding RNA space has been in an ongoing renaissance since 2020. However, as the themes from the past year suggest, we are becoming a much more well-rounded industry. Yes, we’ve started to see more preclinical and clinical data released for mRNA products outside of the prophylactic vaccine space. But I’d argue we’ve also become an increasingly self-reflective industry — one that’s started to slow down to take stock of how and more specifically where our RNA products fit into the broader biologics and ATMP ecosystem. And that’s certainly a development worth celebrating.

1. mRNA Is Learning To Play Nice With Others

After attending a conference in July 2023 that made me feel like Alice in an mRNA Wonderland, I published an article outlining three challenging realities of working with mRNA.

One of those three takeaways was this: The “Academy” is still out on whether our mRNA therapeutic products will be nominated as “the best actors” or the “best supporting actors.”

To be fair, we don’t know yet what most of our preclinical products can do clinically. Depending on the indication, they may be the “best [therapeutic] actor.” But over the past year, we’ve started to see mRNA take the stage as a highly “collaborative” modality. We can see this “collaboration” taking shape in a few different therapeutic arenas. Obviously, some of the best — and most high profile — clinical data we’ve received in the past year have been for BioNTech/Regeneron’s & Merck/Moderna’s respective individualized mRNA cancer vaccines, both of which are in combination with the mAb immunotherapy Keytruda.

But we’re also starting to see more preclinical data showcasing the power of mRNA in combination with other modalities in the ATMP space. For example, the mAb-mRNA pairing is also being explored in the world of base-editing, thanks to Beam Therapeutics’ ESCAPE program. In Beam’s program, which just released NHP data in early November, an antibody therapy is used as a conditioning agent in place of busulfan (which, side note, was actually linked to a death in one of Beam’s trials this year).

I was also struck by Metagenomi’s NHP data from a few weeks ago that comprises an AAV gene therapy approach followed a few weeks later by a dose of an mRNA-encoded nuclease/LNP and guide RNA. (I know, right?! Wild times.)

We often talk about the importance of partnerships in development because we can’t always do it all by ourselves. But clearly, the same can be said for our therapies. One of the biggest challenges we have before us is identifying mRNA’s unique therapeutic strengths. After 2024, she seems to be showing off her burgeoning abilities to be a kick-ass team player.

2. Our Drug Substances Are Getting More Complicated

In 2024, we saw some of the next-gen versions of encoding RNA advancing through preclinical or into clinical development.

In the case of saRNA, we celebrated the approval of the world’s first saRNA vaccine in Japan earlier this year, thanks to Arcturus Therapeutics. We also saw Strand Therapeutics enter the clinic with an saRNA oncology candidate, and Replicate Therapeutics released interim Phase 1 data for its saRNA rabies vaccine.

On the circular RNA front, Circio, Orna, and Sail Biomedicines all released preclinical data this past year demonstrating that circular RNA can do what we’ve hoped it would (in animals): Offer improved/extended protein expression compared to linear mRNA.

But beyond the “brand” of RNA with which we’re working/packaging, we’re also starting to explore products that comprise multiple mRNAs encoding different proteins or protein complexes. Not to mention, as we shift to therapeutics, we’re striving to express more protein in vivo compared to prophylactic vaccines, which only require a minimal amount of protein expression to be effective. Of course, such molecular complexities naturally raise big questions about manufacturing efficiency, analytical development, and overall quality. But in the past year, our more complicated encoding expectations have, naturally, started to raise more questions about in vivo translation. For example, I think it says something that one of my top-performing and most-shared LinkedIn posts of the past year was to a press release about Pfizer/BioNTech’s trivalent flu vaccine. As the companies reported at the time, the vaccine, which was designed to protect against Influenza A & B and COVID-19, failed to sufficiently protect against Influenza B — a result suggesting not all proteins are created equally in vivo.

To be clear, this isn’t necessarily “new” news; mRNA translation heterogeneity was the topic of this Trends in Cell Biology article from 2020. But Pfizer’s news came on the heels of a presentation at the World Vaccine Congress, at which another mRNA vaccine company shared data from a multivalent vaccine candidate indicating that certain mRNA “speak their piece” (i.e., encode their protein) more readily than others. Likewise, translatability was singled out as one of the biggest challenges keeping the panel of executives I interviewed at the World Vaccine Congress awake at night.

We say it regularly and often in the scientific field: The more we learn, the more questions we ultimately have. Our advancements toward the clinic with next-gen RNA modalities, combined with more ambitious therapeutic goals overall, demand we start asking more nuanced questions about our products — and 2024 indicates we’re well on our way to a more inquisitive future.

Part 2 with the final three developments of 2024 coming next week—stay tuned!