Translatability: The Challenge Keeping mRNA Therapeutics Execs Up At Night

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

In my previous two Advancing RNA editorials, I’ve looked a bit deeper at the myriad shapes partnerships are taking today in the RNA space — whether it be the critical biotech CDMO partnership or partnerships with academia or delivery platform companies. These insights were gleaned from a panel discussion at the World Vaccine Congress, during which four RNA C-suite executives — Gilles Besin, Kate Zhang, Gopi Shanker, and Andy Geall — all made irrefutable points about the nascence of the space and the importance of the partnerships we’re establishing today. But there is one critical “relationship” we still haven’t quite unpacked — and it’s one that remains frustratingly enigmatic and alluring all the same: The relationship (or perhaps “partnership”) between our drug products and the human body.  

The great mystery of our products’ structures and functions shouldn’t be surprising, considering we’re a heavily preclinical industry and our most “mature” clinical proof points have been for prophylactic vaccines. As we transition toward therapeutic applications of mRNA (which demand targeted delivery and selective expression), several of the experts on the panel pointed to the formidable challenge we face in understanding the cellular environments into which we’re delivering our drug products. Figuring out how to get our products to and into the appropriate cells is only just the beginning; once they’ve arrived to/in the cell, there are many yet unknown cellular dynamics that go on to influence the “survival” and performance of our products.

It goes without saying — but is still worth repeating — that there’s a lot we need to understand about how our drug products’ composition (i.e., lipid/mRNA ratio), analytical profile, and manufacturing process impact their potency and safety. But I also appreciated the panels’ focus on the importance of gaining a clearer understanding of the biological factors that influence the strength, durability, immunogenicity, and overall deliverability of our RNA therapeutics.

Considerations For Minimizing The Gap Between Mouse & Human mRNA Translation

I’ve heard it said before that, regardless of modality, preclinical models leave a lot to be desired — and the mRNA space is no exception. In fact, Besin’s previous experiences working within the DNA vaccine space reinforce the concerns he laid out during our RNA-centric panel: Mouse and nonhuman primate models only tell us a small part of our product’s clinical story. So, when I asked each expert to elaborate on one of the biggest challenges keeping them up at night, Besin and Zhang were united in their concerns on translatability.

“Though there have been some improvements, there’s still a lot of work to be done on creating the appropriate preclinical models,” Besin said. “Finding the right model to demonstrate the efficacy of our mRNA & RNA products is a very big challenge and is one of the biggest issues keeping me up at night. Working on the animal model is very important today — in fact, maybe it’s not an animal model, maybe it’s an in vitro human model.” Afterall, as Shanker reminded us, some of the indications we may be striving to address require targeting/accessing cell types that only exist in the human body.

Coming from the delivery/LNP side of the equation, Zhang reaffirmed Besin’s concerns about the varying degrees of translation we can see from mouse, to NHP, to human models. But for a delivery company, the question goes beyond cross-species translatability; there will also be differences in delivering to healthy vs. diseased cells, as well as the mechanism of delivery (i.e., passive vs. active). Optimizing composition and the formulation ratio will play a critical role in our products’ specificity; however, Zhang maintains that the lipid structure itself plays a significant role in achieving the specificity we want/need to have the desired clinical effect. As she explained, building libraries of diverse lipid structures that complement different cargos and target different organs and cell tropism is only one piece of this equation. It’s also important to keep in mind the different dosage needs the different therapies will demand and the underlying safety of that approach.  

“A high-dose gene editing therapy may push the boundary of those lipids and how much the human body can take,” she clarified. “You may have to adapt for multiple doses. These are the types of things you have to change when designing your therapeutic index.” (A really great example we’ve seen of this in real life so far is Verve’s decision to switch its lead gene editing candidate’s LNP following LNP-related toxicities in a clinical trial.)

I loved the analogy she created to describe the extent of the challenge facing us today — one which demands we optimize the physical characteristics of our produce to target and “unlock” the cellular environment in which they need to do their important work. As she explained, we can think of our product as a plane traveling across the Atlantic Ocean to the East Coast. But we must continue to drill down our “final destination” — identifying not only the state, but the city, the neighborhood, the specific apartment building, and, finally, the individual apartment/address (the door to which, of course, will have its own unique key to access).  

“I’m hopeful LNPs will do 80-90 percent of getting us to the right place, and then maybe ligands, antibodies, and/or peptides will help us cross the threshold of that final destination,” she concluded.