So mRNA…

It was the first day of the American Peptide Society conference, and the keynote speaker was Mellisa J. Moore, CSO of Moderna. It was wonderful to hear and be reminded of all the past research that enabled the development of mRNA vaccines. I suppose developing a therapeutic or new method that everyone in the world will benefit from is something all of us dream a little about.

Everything of course starts with the discovery of mRNA some 60 years ago, then it’s followed by a big setback where the immune response against external mRNA is discovered. Prof. and Senior VP of Biontech, Katalin Karikó, found that you could replace the uridine with modified uridine and avoid the immune response. So mRNA could again take off, but how do you deliver, which mRNA codon combination do you choose, and what happens to the lipids after the nanoparticle is merged… There were still so many steps to optimize and so much about biology to learn.

Moore has mentioned that it took them 1h to design the mRNA that made it into the vaccine. Spike protein is huge, over 1000aa. So you have many mRNA sequences to choose from. The modified uridine adds more stability; you have to balance and make its secondary structure a little less stable in order to get the desired expression rate. So it’s not as simple as you are going to choose the codon combination that is most abundant in humans. And to be able to choose one within an hour is amazing. They have a computational model to do that which is what makes it even more amazing. They have generated the required data to build that model, they published an article about it, and now they can use it to design an mRNA for an enormous protein within an hour.

After the success of the mRNA vaccines, it is not surprising that Moderna has many other applications in the pipeline. Being able to target intracellular protein-protein interactions has been the dream of many. But crossing the bilayer is not easy. The mechanism of action of many peptides that cross isn’t always clear. Do they passively diffuse through the membrane? Doesn’t seem likely. Are they going through endosomes? If so how do they escape without being degraded? … Many questions to ask, but so few answers you can get. When everything is a blur, designing peptides that will cross the barrier becomes an even bigger challenge.

mRNAs don’t have this problem. They cross the barrier thanks to the lipid nanoparticles. While one can argue that lipid nanoparticles aren’t specific, well they can be made to be more specific. At least there is research on making them more specific. You deliver one peptide, you block one protein-protein complex. You deliver one mRNA, and you block several protein-protein complexes. So they also have the advantage on that front.

When mRNAs seem like the golden child it makes you wonder is there a role for other modalities? Is there a need for peptides or small molecules… In the short one, yes, but in the long run is there? I am keeping antibodies out of this category as they can recruit the immune system and eliminate the target. LNPs haven’t crossed the blood-brain barrier yet (if I remember the response at the talk correctly), so maybe for targeting the central nervous system you still need peptides or small molecules. But it feels like it’s just a matter of time before a discovery is made to enable it clinically. So back again to the question, is there a need for peptides or small molecules as therapeutics? Not as delivery agents, but as actual drugs, are there?

As you may have guessed the talk was thought-provoking. I won’t stop working on peptide therapeutics right this instant and so won’t the field. Yet it’s impossible not to ask the question. Anyways, it’s midnight here, and 3 am in Toronto so well past my bedtime. I’ll keep thinking about this question and do more research later.