The huge success of the mRNA vaccination platform during the pandemic has set a lot of people to thinking about what comes next. Moderna and BioNTech, of course, have been thinking this way for quite some time. But Sanofi now says that they’ll be investing large amounts into the technology, and this previously hadn’t been a big priority for them. There are others as well. So let’s step back a little and look at what mRNA can do and what it can’t.
Therapeutic mRNAs
The first distinction is between vaccines and therapeutics. It’s hard to remember now, but Moderna did not really start out as a vaccine company – they were going to make mRNA-based therapeutics, and there are some key differences. It’s an exciting idea to reach into the body and tell particular cells to start making particular proteins (of your choice) by sending mRNA messages into them. You can think of a lot of possibilities, but there are a lot of difficulties along the way to realizing that.
For one, you’re not taking advantage of the memory that the immune system brings, which is what lets you vaccinate for a brief period and then have months, years, maybe even decades of protective effects. This sort of mRNA work isn’t immune-driven at all, in theory, and if you need your target cells to keep producing your desired protein, you’re going to have to keep telling them that by sending them more mRNA. Once a day? Once a week? Who knows? That’ll need to be worked out by experiment.
A second problem is that “not immune driven” part. If you go back to the earliest attempts to treat cells with external mRNA constructs, the people running these experiments weren’t trying to set off an immune response – they were trying to do that “make me a protein” trick. But foreign mRNA can be very immunogenic indeed – the innate immune system is constantly watching for various foreign nucleic acid species as a sign of infection. In fact, one thing that had to be worked out for the vaccines over the years was how to turn down that immediate immune response so that the more long-lasting adaptive immune one had a chance to kick in. (As mentioned in this post, that may well have been what sank the CureVac mRNA vaccine, which will continue to stand as a demonstration that mRNA technology is not the Magic Road to Efficacy. Nothing is the Magic Road to Efficacy). So if you’re going to give patients an mRNA injection and you don’t want to set off alarm bells in the innate immune system, you’re going to have to carefully engineer your sequences at the very least.
But remember, you’re doing all this to force the cells to make some protein that they weren’t making before. That’s the point of all mRNA work. What if that protein is sufficiently foreign-looking that it sets off an immune response of its own? Well, whether you felt like it or not, you have now vaccinated people against it, so if you wanted it to be produced undisturbed to do its work, that’s a problem. There’s going to be a window you can work in: an all-human protein sequence should be fine, but the more modifications you make after that, the greater the chance you might trip one of the alarm systems, at least in a few patients. The immune response is hugely variable from person to person, and the response to a foreign protein can range from nearly silent changes in circulating antibody profiles (at one end) through skin rashes and other allergy symptoms, then into things like the myocarditis and clotting effects seen with the current coronavirus vaccines in small numbers of patients, up to sudden anaphylactic shock and potentially death (think of people who are hugely sensitive to penicillins, peanut antigen proteins, or bee stings). Animal studies can alert you to some of the alarming outcomes, but the only way to really establish the levels of these sorts of things is with human clinical trials. And maybe not even then: as the vaccine work illustrates, no clinical trials are large enough to pick up the truly very-rare-but-serious things, which makes development rather fraught.
A third problem is targeting. As has been mentioned in previous posts, the lipid-nanoparticle mRNA vehicles tend to pile up in the liver above all other organs. That’s no particular distinction; most things we dose people with in this industry either pile up in the liver or get shredded to some degree each time they pass through it. But we have no good ways to inject someone with mRNA constructs and send them to some particular tissue without dosing every other tissue in the body. As with antisense, CRISPR, RNAi, and other exotic nucleic-acid-based technologies, the two ways that people have slid past that problem have traditionally been (1) pick a disease of the retina, because you can inject into the eye and things tend to stay there or (2) decide that you wanted to treat a liver disease anyway and just roll with the fact that that’s where your stuff is going to go. The recent human CRISPR results take that second route, which is exactly the route that the first RNA interference-based therapy took as well.
Now to the big overarching fourth issue: you need to identify diseases that can be treated by causing some particular protein to be expressed in the first place. There are quite a few possibilities, but there are also plenty of diseases where we have no handholds of this sort at all. One of the most obvious ideas is to pick a genetic disease where a less competent (or downright nonfunctional) protein gets produced, and alleviating that by making cells produce the right one instead. If you do that via mRNA, though, you will presumably be making the good stuff on top of still making the original bad stuff, whereas if you do it by CRISPR or some other genetic engineering technique, you will switch over (permanently?) to making the good stuff only. So the genetic approach has that big advantage, with the warning that you’d better be really sure that you’re making the change you want to make. For something like sickle cell or PKU that’s pretty clear, but as you get out of the list of molecular diseases it can become less so. As alluded to above, you can also imagine getting cells to make some enhanced or altered protein instead for some other function entirely, but things get tricky here very quickly. We do this sort of thing all the time in a research setting, but using these things as therapeutics is a big step, and there are far fewer immediately actionable stories in this category.
To get an idea of the complications, stop thinking about sickle cell and start thinking about (say) Alzheimer’s. What protein would you want neurons in the hippocampus to start expressing in order to alleviate Alzheimer’s disease? The only honest answer is “We have no real idea”, because we’re still arguing about what causes Alzheimer’s in the first place, which necessarily means that we’re also arguing about what to do about it. How about Type II diabetes, then? We know a lot more about the mechanisms involved in that one, although there are still some key mysteries. But what particular protein would you want expressed in order to alleviate it? Here at least you can think of a list of ideas, but it’s safe to say that they’re all going to be steps into the unknown when you try them out in patients. You’re also going to be up against some pretty well-characterized small molecule therapies, and in an area with significant safety standards on the regulatory end – so it’s no wonder that people are trying other things first for that disease.
But that still leaves you a lot of room to work in. What other diseases do we treat by administering some external protein? How about all the monoclonal antibodies out there? You could imagine getting your own cells to make those instead, and that’s being looked into. In these cases you already have a lot of clinical validation thanks to the existing antibody drugs; you just have to work out if your endogenous route is effective and what advantages it might have. That’s plenty of risk for anyone, but at least the targets are solid.
mRNA Vaccines
Vaccines are of course aimed at producing a durable immune response – you have a short series of injections to achieve this, and then the memory functions of the immune system take over for lasting protection. Immunizing against some sort of foreign protein found in a dangerous virus or bacterium is the most obvious way to work this – it’s absolutely the most straightforward use for mRNA vaccination, and that’s exactly what Sanofi looks to be targeting. As we can see from CureVac there are ways for it to go wrong, and as we can see from malaria or dengue there are pathogens that are very difficult to find effective antigens to use as the basis for immunization. But overall this is still the most solid bet, by a huge margin.
The therapeutic opportunities for siccing the immune system on targets inside the human body are limited, to say the least. Years ago I saw a presentation from someone who was trying that with adipocytes for weight loss, and my eyebrows nearly escaped my head – even now, I have to remind myself that this was not some weird dream. No, what you want is (somehow) a source of foreign (or foreign-ish) proteins inside the human body. Hmm.
How about targeting some sort of protein found on the surface of particular cancer cells, and turning the immune system against those instead? That’s not a new idea. It’s been tried quite a few times over the years, but rarely with much success, immunology being what it is and oncology being what it is, too. It’s true that immuno-oncology has been a very hot topic for some years now, but that’s partly because successful approaches were found that did not depend on trying to find a way to directly immunize against cancer cells.
The closest thing we have is CAR-T, chimeric antigen receptor T-cell therapy. As you can tell from the name, that’s not an antibody-driven approach at all, but rather uses T cells on the attack, and instead of a vaccination to rouse them (which hasn’t really worked), it’s a much more laborious procedure that engineers a patient’s own T cells to deliberately recognize some particular surface antigen on the targeted cancer cells. It works for some kinds of leukemia (and not always then), and the successes are due partly to leukemia cells being individually accessible out in the bloodstream, and very much because some key antigens have been identified that lets these cells be specifically attacked. Even then, your leukemia cure likely comes at the cost of permanently impairing the population of the leucocytes involved. That’s a real concern, but if you’re to the point of doing CAR-T your alternative is basically death within months, so it’s a worthwhile trade. Naturally, people are working on other specific ways to mobilize T cells as well.
Finding markers that are even that useful for solid tumors has been difficult, though – there’s nothing to say that it’s impossible, but it’s definitely hard. So a first problem has been finding good antigen candidates in the first place, and mRNA tech in this case is just a neat way to get that antigen delivered. A second problem is the selectivity of any of these candidates in the real world. This is the other side of the sword when you’re letting the immune system do your work: if you turn it loose against the wrong things, the consequences can be catastrophic. And the aforementioned variability of the human immune response will always have you tiptoeing around in the clinic. What if the occasional patient mounts a vigorous immune attack on their own islets of Langerhans , or their own hepatocytes, or their own peripheral motor neurons? There’s only one real way to be sure, unfortunately.
And those issues, among others, are what has kept the cancer vaccine field from taking off, mRNA-powered or not. Pre-pandemic, Moderna was working on these, and no doubt they still are. But whereas we could go from “new pathogen” to “new vaccine” in about a year (an amazing feat, to be sure), developing any similarly effective cancer vaccine is already in the “decades and counting” category. There’s a huge amount of promise in this area, but don’t expect it to zip along like a viral vaccine might be able to.
Perspective
So mRNA-based techniques have a lot of power and a lot of promise. But there’s definitely a low-hanging-fruit area here, and that’s infectious disease vaccines. Beyond that the promise holds up, big-time, but the difficulties mount up as well. It’s going to be a long story with a lot of plot twists, but I’m glad we’re telling it.
The post What mRNA is Good For, And What It Maybe Isn’t first appeared on In the Pipeline.
