Biotech companies, investors pour billions into mRNA vaccines as research ramps up in cancer and non-communicable diseases

Michelle Brown: Near and dear to my heart, since I’m the program lead for the cancer vaccine portfolio, is that you can leverage this technology to really generate different therapeutic approaches for oncology. What you see across the mRNA platform is this adaptability. 

But importantly, what we learned with COVID, too, is that you have this immediate breadth of scalability. So, before 2019, Moderna had only dosed several thousand patients, and what we know where we’re sitting today is that we’ve administered over a billion doses.

So, that really tells you how scalable this platform can be, and I think that that is the true sort of nature of what’s required when we think about a personalized cancer vaccine approach, is we need adaptability, and we need scalability.

One of the nuances here is that it really does require this integrated manufacturing to enable speed and customizable attributes. Our personalized cancer vaccine is called mRNA-4157. It is designed to activate and target each patient’s immune system, to target their unique tumor mutations. 

The goal is to assess, just like a fingerprint, each patient’s unique tumor mutational profile. We do this by taking samples, and we do this through a needle-to-needle process. 

We start with a collection of the tumor and normal tissue to identify tumor-specific mutations. And what you’ll get with this next-generation sequencing approach is a litany of mutations, hundreds, thousands. 

And they’re not necessarily all meaningful, because they don’t necessarily all generate an immune response. They’re just aberrant.

So, we used a proprietary advanced computational algorithm to really sift through the noise of all of those mutations to identify the ones that will actively train the immune system to recognize the tumor. 

And by training it, we’re actually activating that patient’s T-cells to go and target the tumor milieu, and mount an anti-tumor response. 

For our vaccine, we use up to 34 neoantigens on a singular mRNA strand to really cover the breath and depth that you would think about for neoantigen spread. 

Because that way, we can get endogenous neoantigen, we can get those that haven’t necessarily been seen by the immune system before, and we can generate epitope spread. 

Once we’ve had those 34 neoantigens recognized, they’re encapsulated in lipid nanoparticles, and essentially, we’ve generated one therapy for one patient. And this is then delivered to the clinic, and administered intramuscularly to a patient.

Now, we’ve seen the sort of schema for what happens once this mRNA enters into the normal cells, it uses normal host machinery. 

So, we take that mRNA, it’s translated into a polypeptide chain, because this is a nonsense protein, it’s a conglomerate of a bunch of different neoantigens, the body doesn’t recognize it, so it slices it up, and those each neoantigen peptides are sort of released.

What they do is, they make their way up to the cell surface, and are presented in the HLA. And this is important because the HLA is what interacts with the T-cells, and trains those T-cells to say, “Hey, this neoantigen is foreign. You need to go out, look for it, and attack it like you would for a foreign infectious disease particle.”

And this is really specific for mRNA technology, because a lot of these neopeptides are normally housed in the cells, so you can’t target them with your traditional monoclonals, you can’t target them with the CAR T-cells, because they don’t normally sit on the surface. 

So, mRNA really gives us the flexibility to show the immune system something that it doesn’t naturally see, so that it can go and target the tumor.

Now, the basis, as we’ve heard, for this technology to mount an anti-tumor effect is really dependent on our ability to stimulate T-cells. And like traditional drug development, we started our study with a phase I study to look for, first, if we could identify a safe intolerable dose for mRNA-4157, but also to look through and see the immune response that we can see. 

So, this is a traditional dose escalation design, we had a monotherapy cohort in adjuvant disease very similarly, because we wanted to look for monotherapy treatment effects, and those that didn’t have big bulky tumors that were with better fit patients.

In addition, we had dose escalation in combination with pembrolizumab. And part of the reason for that combination is because, if you imagine, the checkpoint inhibitors are vastly activating the immune system, and with mRNA technology, what we’re doing is targeting and activating and exposing, so we’re directing that immune response towards the tumor. So, it’s hypothesized to be very synergistic.

Also, because this is a targeted effect, and because these neoantigens aren’t expressed on normal cells, what we would expect is a more tolerable profile than other combinations, like we see with other combinations of checkpoint inhibitors. In this study, again, our objective was to assess safety, get a dose, which was then used in our phase II study, and to assess the patient mechanism of action, to see if our hypothesis was correct. 

This is a representative example of a non-small cell lung cancer patient that was treated in the monotherapy cohort. They have their blood drawn at baseline before they had treatment, and then after four cycles. What you see across the bar is the different neoantigens that were included in their personalized cancer vaccine. And what you see on the Y-axis is their robustness of their T-cell response.

The gray bars are what was present at baseline, and the red bars are what’s present after the PCV administration. And what you see is that the majority of the antigens were able to elicit an immune response, so we are activating T-cells. This gave us confidence that mRNA could truly stimulate the immune system the way that we had wanted to. 

So, the question then became, “Okay, if we are stimulating and activating the immune system, and we know that an active immune system results in anti-tumor effects, how do we prove this? How do we test it?” 

We looked through a multitude of tumor types, and one of the tumor types that came up on the top of the list was melanoma. And the reason was, back in 2019, if you think about it, the first is that there’s a biological rationale for melanoma. It’s a UV-mutated tumor. There’s a lot of neoantigens—they’re pretty sloppy—because there are a lot of mutations. So, there’s going to be a lot of neoantigens to choose from for the vaccine.

But also, in 2019, the entire treatment landscape in melanoma was shifting. We knew the checkpoints were coming on board. We also knew that this was a very immune-sensitive tumor, so if we were going to see a treatment effect, we should be seeing it here in the melanoma space.

The other thing that we knew was that in the adjuvant disease setting, these patients were looking like they were doing well because we had Keynote-054 rehab. So, Keynote-054 was in stage 3, high-risk resected patients, and it served as the foundation for pembrolizumab’s label. So, it compared pembrolizumab to placebo, because there was no standard of care at the time, and what you can see is a massive treatment effect based off of the blue line, really solidifying how effective the PD-1 inhibitors are in this disease setting.

Unfortunately, what we also saw was that by a year, about one in four of these patients had a recurrence of their disease. And by five years, what you see is that about half the patients have a recurrence in their disease. And this is important, because this recurrence in this patient population results in significant morbidity. It can result in metastatic disease, which then comes in with mortality risks, and obviously, there’s an impact to quality of life. 

In addition to the significant unmet need in this population, we know that they’re disease-free, because their tumors have been resected. And so, there’s an importance for tolerability, because you want to maintain quality of life—essentially, we’re looking at cure.

When we looked and thought through where we wanted to test our personalized cancer vaccine, we wanted a setting that was immune-sensitive, that had a significant unmet need, but also where tolerability was really important, which was the genesis of the Keynote-942 study.

So, this is the study that we announced back in December that met its primary endpoint. This was a randomized phase II open-label study in resected high-risk melanoma, stage 3-4 patients. It’s in a collaboration with our collaborator, Merck. Patients were enrolled on this study in a two-to-one ratio. 

We treated about 100 patients in our combination, pembrolizumab and mRNA-4157 treatment arm, and about 50 to standard of care for pembrolizumab. And importantly, because we know the manufacture of vaccines takes time, you know it only takes a couple of weeks to get these patients to have their personalized approach developed. 

All patients started treatment with pembrolizumab, and for that combination arm, that meant that they had about two cycles of PD-1 monotherapy, then they continued on for about nine cycles with the PCV combination, and then they continued on with pembrolizumab maintenance.

The primary endpoint here was recurrence-free survival, very similar to what was seen with 054. And here, we tracked patients for 12 months as a minimum, and looked for a minimum of 40 RFS events. The trial had completed enrollment in September 2021, and then as we heard in December, we met our primary analysis objective of improving recurrence-free survival. 

So, what we saw was that the combination of our personalized cancer vaccine with pembrolizumab reduced the risk of recurrence or death in these patients by 44%. We had a hazard ratio of 0.56, and if you remember from what I just showed you for the Keynote-054 study, that hazard ratio was 0.61 versus placebo.

Essentially, our treatment effect, on top of what is currently standard of care, is better than what had been seen in the past. In addition, our one-sided p-value was 0.026, and based off this statistical design in this protocol, this is statistically significant. So, we were very excited in the December timeframe to see such a profound treatment effect. 

But, importantly, what we were also very excited about was that the adverse events we saw for these patients were very consistent with what we had observed in the phase I study for mRNA-4157. So, whoever’s had a COVID shot sort of knows the adverse event profile we’re talking about. 

Importantly, what we also saw is that we didn’t change the nature of pembrolizumab. Pembrolizumab behaved like it has been reported in this disease state, and very importantly, for these patients, we didn’t see an increase in clinically meaningful adverse events. So, with this study in December, what we saw is that we have an effective therapy that’s safe and tolerable. 

What does this mean? The Keynote-942 study is really the first demonstration of efficacy for an mRNA cancer treatment in a randomized clinical setting. It’s also the first active treatment to show improvement on top of PD-1 in the adjuvant setting, because we know the PD-1s are very active. 

So, this is very encouraging for the potential for mRNA, because it provides a proof of concept that a personalized cancer vaccine approach, and a neoantigen patient-centric approach can generate meaningful clinical responses. It also shows that mRNA has a play outside of infectious diseases.

And because this is a personalized approach, and even though the study is in melanoma, what this means is that we have a lot of hope for oncology patients as a whole. And, importantly too, because the mechanism of action is so novel, we’re not just adding on to what’s currently out and available, nor are we taking away from patients’ options that they could have in the future, we’re really introducing a new therapeutic and a new modality in the oncologist’s arsenal. 

And then what was announced based off of the P201 data, and the reasons I just said, the FDA designated us with Breakthrough Therapy Designation about two weeks ago.

So, where are we going? Based on the FDA Breakthrough Designation, we know that we have quite an aggressive development strategy for mRNA-4157. The first thing we’re doing is continuing to develop this asset in collaboration with Merck. 

The second thing we’re doing, which is important, is that we’re going to disclose the full dataset from Keynote-942 in an upcoming oncology meeting, and a peer review publication. That data is pending. In addition, the P201 study is not done. We did the top line, we have data, we’re going to share the data, but we are still tracking those patients, we’re collecting more data, we’re going to see the long-term outcomes. And so, we continue to learn and we continue to look forward to seeing how these patients do.

In addition, what we know is that this was a phase II study, and we plan on launching full registrational intense studies. We have announced that there will be a phase III study launching this year, and in adjuvant melanoma, and this will also expand into tumor types that have similar features—similar inflammation, similar high-neoantigen burden; really in a similar disease setting. 

So, we think through this, and some of those tumor types look like non-small cell lung cancer. We are going to be very aggressive to try to get this therapy out to as many patients as we possibly can.

And those are just the registrational studies. What we also know is that there’s a lot of biological rationale, and there’s a lot of potential for a personalized neoantigen approach. We will look through the litany of tumor types, and assess those that are immunosensitive, and also other settings where we can really try to make an impact. 

So, I think the key is that mRNA has a lot of potential, not only across from the platform, but also across the different stages of disease for oncology. We’re very excited to see what this new era of mRNA technology is going to bring.

Mahesh Yadav: The focus of today’s talk is how we are thinking about targeting neoantigens, which I will get into in a bit to harness the immune system to fight against cancer. And for this we have a collaboration with BioNTech since 2016 on an exciting personalized approach to cancer vaccines using the mRNA platform.

Neoantigens, these are cancer specific mutations that are present in almost all cancer cells, but not on the normal cells that’s shown here. On the left side is a wild-type, a normal cell, the wild-type protein with the sequence. 

And in the cancer cells this sequence is altered. You have a mutation in one of the genes which leads to this secretion or production of this protein, which is an altered form. And this altered protein is seen as foreign by the immune system and T-cells can recognize these proteins or the neoantigens and kill the cancer cells that are expressing these mutations. 

At Genentech, we are taking two approaches to target neoantigens: First is the cancer vaccine, which I will focus on today, and the second, we are working on using the T-cell therapy platform to target neoantigens in cancer patients.

So, why do we still believe in cancer vaccines? They have been around for a long time. Why do we think it’s time to revisit cancer vaccines? Making cancer vaccines is extremely hard, and previous vaccines have failed due in part to poor antigen selection or suboptimal platforms.

But it is different this time with the identification of tumor-specific mutations or neoantigens as the main driver. We have this new class of antigens that we can target using cancer vaccines. There are new platforms which are much improved than the previous one, e.g. RNA-based, which we are discussing today. But there are also viral vector-based and DNA-based platforms. 

And there also have been recent advances in technology such as next-gen sequencing, which allows you to identify these specific antigens, neoantigens, in this case. There are better tools for immune monitoring. Finally, we have these existing immunotherapy approaches that cancer vaccines can build on.

Why are neoantigens a great target for cancer vaccines? What you need from a cancer antigen to be part of a vaccine are two things: One is the expression specific to the cancer cells, and two, are the foreigners to the immune system.

If you think of these two criterias compared to other types of cancer antigens, neoantigens ranked very highly for both of these. So, that makes them really suited for a cancer vaccine approach. But one challenge with the neoantigen vaccine is most tumor mutations are unique for each patient. 

That means each vaccine has to be uniquely tailored for individual patient, which is a big advance—we’ve used drugs for groups of patients, but with the neoantigen vaccine, what you’re looking at is an individual drug product that will be made to order for the individual patient and can only be used for that specific patient.

Just a quick word on what other platforms are out there. One of them is the cell-based cancer vaccine. In this case, the antigens are loaded on immune cells like dendritic cells and given to the patient. Then you have the viral-based cancer vaccine. In this case, the engineered viruses are used as vectors to deliver tumor antigens to the patient. And one of the oldest forms of cancer vaccines is still peptide based. In this case, these antigens are expressed as polypeptides and then given to patients. 

The nucleic acid-based cancer vaccine, both mRNA and DNA, these are the recent ones. Genentech is actively pursuing both of these—the mRNA cancer vaccine, also called autogene cevumeran, in collaboration with BioNTech; and we also have a collaboration with Nykode to utilize their DNA vaccine platform.

What are the advantages of using the mRNA platform? Why are we so excited about this? First, the overall immunogenicity of mRNA vaccines seems higher than other types of cancer. 

The mRNA vaccine can be easily programmed to deliver the genetic information and coding antigens in the form of messenger RNAs. So, it is possible to achieve individualized manufacturing for patient specific vaccines. And then there have been recent modifications that make it feasible to increase the stability and also reduce the cost.

And this is a summary of just comparing the mRNA COVID vaccine with the cancer vaccine, in this case, autogene cevumeran. The COVID vaccine uses the modified mRNA complex with lipid nanoparticles. In the case of the cancer vaccine, it’s unmodified mRNA in these lipid molecules called lipoplex formulation.

For the COVID vaccine, you use a fixed vaccine sequence. It’s a known viral antigen, so likely to be very immunogenic. And then, it is designed generally to induce antibody responses—versus the cancer vaccine, every antigen is different because every patient has a unique set of antigens. So, it’s uniquely designed for each patient. 

The tumor neoantigens are not proven to be immunogenic, and it’s designed to generate T cell responses, unlike the viral vaccine, which is mostly inducing antibody responses. The COVID vaccine is given intramuscularly, whereas the mRNA vaccine is given intravenously.

Here is the overview of the workflow used for designing the cancer vaccine. Generally, a patient tumor is taken out, which is then sequenced genetically to identify these operations or the antigens. Once the mutation or these alterations are identified, a software is used to predict which of these are most likely to generate a strong immune response.

Once that list is identified, these are put in this mRNA molecule shown here. You can include up to 10 different neoantigens in this molecule. And then these mRNA, two of these, for a total of 20 neoantigens, are then complexed with these positively charged lipids into a liposomal formulation for the IV administration.

Testing of cancer vaccines in the clinic is really challenging. If you think of the success of the COVID vaccine, it’s really challenging to develop a therapeutic cancer vaccine. For viruses, it’s a viral antigen, again, obviously very foreign to the immune system, and most of these vaccines are used in preventive settings. Whereas cancer, it’s an evolving disease which already is very heterogeneous and advanced.

So, the question is, can we find a similar setting in cancer patients where we can use the vaccine? And I think this is where we think patients with minimal disease—these are the patients that have recent resection of the tumor—might be ideally suited for a cancer vaccine.

And shown here, if you look at this graph showing the transition of cancer from early to the advanced disease in early cancer, you’re likely to find less heterogeneous disease. Patients are likely to have an intact immune system, because they have had fewer prior lines of therapy. You are also able to achieve this favorable ratio of T-cells induced by the vaccine compared to the tumor cells. 

So, we have different programs ongoing to test this vaccine in the clinic—top two are testing the vaccine in advanced stage cancer patients, and BioNTech has a trial in early-stage colorectal cancer, patients who are at high risk by ctDNA positivity. 

And then there is an investigator-sponsored trial run by MSKCC to test this vaccine, autogene cevumeran, in pancreatic cancer patients. That’s the one I’m going to focus on.

So, treatment of PDAC pancreatic cancer or PDAC patients is really difficult. It’s a very aggressive form of cancer. It’s very hard to treat, and most patients do not respond to the treatment. In fact, after resection, most patients relapsed within months.

The question is, can induction of neoantigen-specific T-cell responses using the mRNA vaccine improve outcomes for PDAC patients? This is the workflow, similar to what I described, used to generate the vaccine for PDAC patients up to 20 neoantigens in each vaccine using two mRNA molecules for intravenous delivery.

So, the patient would undergo resection to remove their tumor and then they will receive this vaccine and followed by their standard of care chemotherapy. 

One thing about cancer vaccines is they will only work if it’s able to generate an immune response. Same thing with the COVID vaccine. If you have a nice antibody response, you’re likely to see protection.

Same here. If the vaccine is able to generate this immune response, you might see clinical benefit in the patient. And because in this case, each vaccine is designed uniquely for each patient, it is really important to monitor if it’s able to generate an immune response.

That’s the question they ask in the clinic. And shown here, in 16 patients they analyzed, what they saw was eight out of 16 patients had an immune response against the vaccine target, shown in the red, and half of the patients failed to generate an immune response against the vaccine.

So, the next question is, is there clinical activity? Which is measured in this indication by looking at the recurrence of disease; remember, these are patients that have resected their tumors, so they have no visible disease. Then, you measured the relapse-free survival, which is the time for the recurrence of the disease.

What MSK did was, since this was a single-arm study, they looked at the patients who had an immune response, versus the patients who did not have an immune response. And what you see in this RFS curve, again looking at the time and month taken for the recurrence of the disease, the patients who failed to generate an immune response—that is, the vaccine—you see that most of these patients have recurrence of disease with a median of 13.4 months.

Whereas, the patients who did have an immune response, you see this nice delay in the recurrence of the disease. It’s a short follow up, but very promising, showing that this vaccine can indeed delay the recurrence of the disease in this form of cancer.

So, just to summarize, neoantigens are mutations in the cancer cells that can be seen by the immune system as foreign and mount an immune response. We can leverage this to generate cancer vaccines which can train the immune system to mount an immune response against the cancer neoantigens. 

Some of the early data suggests that this vaccine is having the desired effect on the immune system and can possibly also provide benefit in some cancer patients treated with cancer vaccines after surgery. 

We currently have other trials ongoing to test this in other types of cancer.

Jonathan Wosen: Everything that happened in the mRNA field in 2020 and 2021 was built on decades of work—going back to the 1960s, when researchers first figured out what mRNA was, working in bacteria, and found that, when you blocked the synthesis of RNA, the bacteria stopped producing new proteins, so there must be some mysterious RNA molecule that’s really important for protein production.

And since then, learning things about how to make mRNA in the lab, as opposed to just in cell, is something researchers are still working on—how to modify mRNA in ways that make it more stable, less inflammatory. There have been trials, studies in lab animals, but then, also trials in people, going back well over a decade.

So, there was a lot of work. This is not at all an exhaustive timeline, but just to give you a sense of how we got to today.

One of the three areas I just want to highlight is the potential for mRNA to be used to power cancer vaccines. Conceptually, you can target the immune system to cancer just as you can target the immune system against a virus. 

For a virus, usually, you’re trying to recognize a particular piece of the virus, and for cancer, you’re trying to recognize what are called neoantigens. These are immune targets that appear on cancer cells. Cancer cells have all kinds of mutations that cause them to produce strange looking, screwed up proteins that contribute to all their odd properties. 

And so, there’s a lot of work happening by a lot of companies to go after those particular antigen targets. Unlike with infectious disease, these are really treatments rather than preventative measures, but it’s still a vaccine at the end of the day.

There are, broadly speaking, two different ways people are going about this. One is to go after what are called fixed antigens, or antigens that are shared across patients, so, a vaccine you can administer to many patients without changing it. There’s also this personalized approach. 

We mentioned personalized medicine at the start, which is a little more involved, because it involves taking a person’s cancer cells, taking their healthy cells, doing some sequencing to see what’s different, using artificial intelligence to look at those differences and figure out what the right ones are to go after. But those are sort of the two things, personalized vaccines, fixed-antigen vaccines. A lot of companies are testing both in parallel. 

Moderna had some good phase II data that they shared back in December from a melanoma trial. They have a number of other vaccines. We may hear more about BioNTech, as well, and a number of other companies. But just to give you a sense that that is going to be an active research space for years to come.

Getting to the second of the three areas that I’ll highlight is protein replacement. Stepping away from cancer for a moment, there are other diseases in which, really, the issue is that our cells are not making enough of a certain protein, or they’re making them right now, but that protein is mutated, it’s screwed up, it’s not behaving properly.

So, in this case, the idea is to use mRNA that codes for whatever that therapeutic protein is. One specific example would be cystic fibrosis, this disease where people have mutations in an ion channel that regulates the flow of ions in and out of cells. They get really severe mucus up in the respiratory tract and their digestive tract, really severe bacterial infections as a result.

There are pretty good drugs for cystic fibrosis, but they only work for about 90% of patients, so the other 10% have mutations that can’t be resolved by current therapies. So, there’s quite a bit of work from a number of companies mentioned here to use mRNA to code for a full functional ion channel. It’s called CFTR [cystic fibrosis transmembrane conductance regulator]. That’s just one example. 

There are a lot of companies that are working on various protein replacement therapies based on mRNA for a number of rare diseases, especially ones where you’re trying to get a certain enzyme produced in the liver. And I’ll talk in a bit about why our liver is a focal point for a lot of mRNA work today. 

The third is going to be gene editing. Just to step back a little bit, you might remember kind of early in the vaccine rollout, hearing rumors or people claiming online that COVID vaccines would integrate into DNA, and modify it. mRNA doesn’t work that way, it doesn’t go back into the nucleus, it doesn’t integrate into the genome, but you can create mRNAs that code for basically any protein you can think of, which includes gene editing tools.

That can include the Cas9 enzyme that cuts DNA precisely at particular sites. It can also include a new set of tools called base editors, which you can think of as a little more like a pencil, which can make single letter or single nucleotide changes in particular areas in the genome. And in some cases, that may be a better fix than just cutting and breaking a gene all together. There are companies that are actively working on all of those things. 

Intellia Therapeutics is one that they’ve had encouraging data readouts for a couple of diseases, where they have shown that you can use mRNA-encoded gene editing tools to do gene edits—inside of a person’s body—that reduce levels of disease-causing proteins. 

Beam Therapeutics and Verve are two companies that are working on that base editing approach, so that’s the more sort of precise single-letter change approach. Beam’s got that for a number of applications that work; sickle cell and cancer immunotherapy are two examples. Verve is working on doing gene editing, basically to treat patients who are predisposed to high cholesterol.

That’s just a little sample that you can use mRNA to code for gene editing tools. And one of the advantages is that mRNA actually doesn’t stick around that long in cells. So, you could deliver mRNA, get these tools produced, have them do their thing, and then eventually degrade, which limits your odds of getting non-specific off-target effects, cuts, and edits in other parts of the genome where you don’t want that to happen. 

So, for any of these applications, at the end of the day, you’ve got to actually deliver the mRNA to a cell, and you’ve got to get it to a particular area of the body, wherever you are trying to send it.

If you just inject mRNA in a person’s body, then it’s destroyed pretty quickly. We have RNA-degrading enzymes in our bloodstream, in our sweat, in our saliva, in our tears, in our mucus, basically everywhere, so you’ve got to figure out a way to protect and deliver mRNA.

Without getting into all the nitty gritty details, one of the main approaches at the moment is basically to wrap mRNA in little bubbles or balls of fat. These are lipid nanoparticles, or LNPs. And in doing so, when these particles get engulfed by a cell, they get sucked into a compartment called an endosome. 

Endosomes quickly become very acidic, pH goes down, and there’s some chemical changes that happen at that point that allow the mRNA to escape or to slip out of that compartment, to get into the interior itself. And at that point, it gets translated into protein.

That’s just a quick snapshot of how that works currently, based on how these lipid nanoparticles are designed, and what happens to them as they’re making their way through the body. 

They tracked it really well to the liver, which is one of the reasons why there’s a lot of work happening to go after various rare metabolic disorders where, if you can deliver a certain enzyme to the liver, we think that’s going to have a good therapeutic effect. Other areas you can deliver mRNA include muscles, lymph nodes, the spleen. But there are a lot of areas where researchers are still working on efficiently sending mRNA.

For example, if you’re trying to treat some neurological disorder, you probably need to get to the population of neurons. Getting to the liver doesn’t really do anything for you, so there’s work on getting to the central nervous system. If you are trying to treat, say, cystic fibrosis, for example, maybe it’s really important to get to the airways. There are companies that are working on using sprays that they can spray to a person’s aerial surfaces rather than intravenous delivery. 

And there’s even some work, still, with the level of mouse experiments for now, where researchers have shown that you can deliver mRNA to fetal tissues. And that might be important and helpful, because, in addition to sending mRNA to the right place, depending on the disease, you may really want to deliver that therapy at the right time—the key window where, if you treat late, you no longer are really helping that patient. 

So, just to say that delivery is, in some ways, still really an active area of research, and may increasingly become one of the big barriers and challenges, as far as I understand, in the mRNA space.

And then, just to give you one other specific thing to think about, there are a lot of people in this field who will tell you that one of the big points in the timeline of mRNA development was figuring out how to modify messenger RNA.

This was work by Katalin Karikó and Drew Weissman at the University of Pennsylvania, in some early experiments, they were seeing that when you put mRNA made in the lab into cells, you got a whole lot of inflammation. You didn’t get that much protein production. It’s actually kind of the opposite of what you generally want. 

So, they spent a lot of time tinkering with the mRNA, looking at different RNA forms, and eventually realizing that there were these naturally-occurring chemical modifications that, when put into our mRNA made in the lab, made it a lot less inflammatory, and also, a lot more stable—and with higher protein production.

RNA is a four-letter language, A, U, G, and C. They basically identified and came up with a modified U, called pseudouridine. That was a big paper in 2005. 

That’s just one specific thing to sort of perpetually keep your news antenna up for, is the Nobel Prize.