From Baby KJ To Global Access: The 3 Pillars Of Next-Gen mRNA Expansion

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

A few weeks ago as I was driving into Philadelphia, a giant billboard caught my attention: On it was a picture of Baby KJ, the first personalized mRNA-based gene editing success story.  I was so excited to see this billboard, I had to make sure I didn’t rearend any of the cars in front of me.  

Oddly enough, the timing of this billboard appearance was quite fortuitous; I was heading to Philadelphia for an event put on by AMM and Franklin Biolabs called Building RNA Medicine Excellence. This inaugural (soon to be annual) one-day event delved into the innovations necessary to enable a future in which more Baby KJs can be treated. Not only did I love the event for its agenda — it boasted incredible speakers including Nobel Prize winners Katalin Kariko and Drew Weissman — but I was also struck by the theme of “expansion” which ran undercurrent to the different conversations.  

Obviously, the transition from RNA vaccines to therapeutics is an “expansion” all on its own; but to do this successfully, we need to expand our science, our products’ deliverability, and our patient access. In the following article, I highlight a few of the best practices and/or innovations that came up in conversation during this event that will play a significant role in helping us expand mRNA’s reach, both scientifically and therapeutically.  

Expanding Therapeutic Possibility   

As you can imagine, AI was part of an overall discussion on innovation in RNA technology. At a base level, we can all understand the promise of AI, but I really loved Profluent’s Hilary Eaton’s discussion of how it will enable us to move beyond the “happy accident” that is our current drug discovery process.

“If we look specifically at editing modalities… we accidentally found them in nature…and [accidental discovery] doesn’t seem like the best way to make medicines,” Eaton said. “In nature, a molecule evolves under various selective pressures to have certain properties. The chance that those properties are the exact fit for the thing you want to treat are very low.”

This panel homed in specifically on protein design — an aspect CHOP’s Mohamad-Gabriel Alameh argued is much more “advanced” than mRNA design. However, utilizing AI for protein design successfully will require us to rely on the tools that have made ChatGPT so successful today — namely machine learning architecture and the availability of high-quality data.

“There are billions of examples of both nature’s dead ends and nature’s successes,” Eaton explained. “Could a model learn the language of proteins? And if so, can you then flip the drug development paradigm upside down? Instead of plucking things from nature and trying to jam them into use cases, can you now say, ‘My use case is the following, and the solution will have exactly these properties. Write me that solution.’ That is a fundamentally different way of approaching drug discovery.”  

In the mRNA space today, we’re predominantly using AI as a tool for designing our mRNA — particularly to improve its durability. As Alameh contextualized, there remains a lot of room for us to use AI for better ORF and UTR optimization to improve our products’ performance in specific cell types. Likewise, as U Penn’s Michael J. Mitchell went on to explain, we can anticipate a lot more work with AI in our quest to improve the precision of our mRNA-LNPs — especially as we set our sights on active delivery.

“One of the issues that we face is we use antibodies, but we have very little control of the immunogenicity or how they get into cells. There’s going to be a lot of work coming out in the next couple of years for AI-generated design of other types of targeted binders for RNA delivery where you can avoid these immunogenicity issues and fine-tune the control of LNP entry into different cell types.”  

Expanding Delivery  

No surprise here, a big way we can expand our product’s therapeutic relevance is going to be by achieving more targeted delivery. Though we often talk about how far we have yet to go, I appreciated each panel’s emphasis on what we’ve accomplished thus far — whether it be delivery to immune cells and bone marrow, or localized administration or inhalable formulations. There is, of course, still much room to grow in terms of targeting the “lower hanging fruit” tissues, including the hepatocytes.

However, as multiple panels went on to discuss, we don’t just have to reach specific organs/tissues; we also need to design mRNA-LNPs that are capable of deeper penetration into those target tissues. And, as U Penn’s Mitchell added, this is “an engineering challenge that targeting is not going to solve.”

There is no skirting the ongoing challenge of controlling an LNP’s morphology, which will impact administration, as well as how it penetrates and performs within a cell. (For more on this, Advancing RNA published this fantastic article outlining recent research into the heterogeneity of multi-cargo LNPs.)

“In a given LNP formulation, most of the LNP’s formulation is junk. It’s not entirely effective if it doesn’t contain any RNA or if it contains the wrong amount of RNA,” Mitchell explained. “There’s a lot that could be done moving forward to reduce the heterogeneity of these formulations,” especially as we shift from vaccines to therapeutics.

Expanding Access  

I loved the following quote from Kevin Strauss of Plowshare Therapies: “We have to jettison this idea that all the innovation and production is going to happen in big university centers and in high resource companies and territories.”

Of course, this quote encapsulates perfectly our goals of expanding mRNA access to countries that need these therapies the most. Though there are several initiatives I could point to that are working diligently on this, I was particularly thrilled for the chance to hear more from Nobel Prize winner, Drew Weissman at this conference who outlined a program he first began with collaborators in Thailand a decade ago. (In fact, a phase one clinical trial in Thailand of a locally produced COVID vaccine revealed better titers than Pfizer’s Comirnaty.)

In addition to building a GMP manufacturing center in Thailand, UPenn also worked with WHO to build GMP sites in 15 other LMICs, including in South America, Middle/Central America, Sub-Saharan Africa, Southeast Asia, and even Ukraine. Each of these sites employs researchers to carry out the essential R&D of vaccines/therapeutics for local diseases like malaria, dengue, TB, and zika, to name a few. Additionally, UPenn will license any of its mRNA-LNP IP to any low-middle income country for free.  

In this age of global development, I also appreciated the reminder from CHOP’s Rebecca Ahrens-Nicklas that rare disease remains a global problem. Not only do we want to ensure that patients in each locale are able to access medical innovations, but it’s equally important we understand that we see the work being done around the world as a treatment opportunity for patients.

“Just like I recruit patients into my clinical trials from all over the world, I want my patients to be able to have access to those clinical trials in other countries,” Ahrens-Niklas said.

Strauss agreed, concluding: “Our job as physicians is to be as educated as we can about what services are available, whether that’s a gene therapy in China or an orthopedic surgery procedure in Argentina, and inform patients and let them decide. Who am I to be a gatekeeper for parents who have a child with a rare disease? If they want to fly halfway across the globe to get access to a lifesaving therapy, who am I to try to dissuade them from that?”