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The State of mRNA Vaccines and Therapeutics
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The State of mRNA Vaccines and Therapeutics
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Language: EN.
Segment:0 .
[MUSIC PLAYING]
JOHN STERLING: Welcome to this GEN State of Biotech session on mRNA vaccines and therapies for cancer and other diseases. I'm John Sterling, Editor in Chief of GEN and I will be your moderator. mRNA became a huge medical topic during the COVID pandemic, turns out that mRNA has a number of other therapeutic applications as well. And that's what we'll explore with our two panelists, let's meet them.
JOHN STERLING: Dr. Nathaniel Wang is Chief Executive Officer at Replicate Bioscience and co-founder of the company. With over 15 years of leadership experience in immunology and drug development, he also is a pioneer in synthetic self-replicating RNA technologies and their delivery. Dr. Daniel Anderson is a professor of chemical engineering and a member of the Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science at MIT.
JOHN STERLING: This past April, Sanofi agreed to provide his lab with $25 million over five years to support efforts to develop next-generation delivery technology for messenger RNA. Dan also is a founder of several biopharma companies. Nathaniel, let's begin with you. What led to your interest in founding a therapeutic RNA company?
NATHANIEL WANG: Yeah, absolutely. And thanks so much for setting this up, John. So in terms of my interest, I know it's hard to remember anything before the pandemic. But people were ready to take RNA technologies behind the shed and shoot them prior to the pandemic actually happening. I think there were a lot of clinical failures in the infectious disease space that were leading up to it. And people had a lot of questions about whether the technology was going to be able to succeed, was going to be able to scale, was going to be safe in humans.
NATHANIEL WANG: And I think what the pandemic showed with a resounding yes, is that RNA technology could do all of those things. It could be scaled. It was very safe in humans, and it could be applied across a wide variety of applications. But one of the things that we realized when we were thinking about Replicate in early 2020 was that a lot of the technologies had started to stagnate, there wasn't a lot of innovation that was going on within the field as it related to some of the newer technologies like self-replicating RNAs.
NATHANIEL WANG: And we felt that one of the things that needed to be done was really to tear the technology down to the studs and rebuild it from scratch. And in doing so be able to make a lot of these engineering changes that the field had long been wanting to make in order to enable them across different therapeutic areas. And so that's what myself and some of our co-founders really struck out to do just before the pandemic hit.
JOHN STERLING: So following that line of thought, Replicate launched two years ago this month. Your stated goal was to amplify the power of mRNA therapeutics by pioneering self-replicating RNA, srRNA technology. Can you briefly describe srRNA technology and how it works?
NATHANIEL WANG: Yeah, definitely so if you think of linear mRNA, and linear mRNA is the RNA that's in the current COVID-19 vaccines, it's an instruction manual that tells a cell how to produce a protein of interest. And so you need a large amount of the synthetic material to be able to produce enough protein to induce the immune response that you want. Self-replicating RNAs in contrast, are an instruction manual that tells your cell how to produce an mRNA of interest.
NATHANIEL WANG: And so you only need a very small amount of that synthetic material. It ends up amplifying the number of fully natural mRNA copies that encode the protein that you want it to. And so you only end up needing a very small amount of synthetic material to be able to produce that therapeutic effect that you're looking for.
JOHN STERLING: So Dan, you have said that mRNA therapeutics have enormous medical potential but new delivery technology is needed to enable their broadest application. Why is this the case and what are the current limitations to mRNA therapeutic delivery?
DANIEL ANDERSON: Yeah. Well, I think as we just heard, we now have proof that mRNA can play a tremendous role as a method of creating new vaccines quickly. But perhaps less well known is there's a growing collection of human data indicating it can also be used for certain genetic diseases, for example, in the liver. mRNA as we know or were taught in our basic biology classes turns into protein in essentially all of our active cells.
DANIEL ANDERSON: And so it's really just a question of how do we deliver mRNA into cells that we want to treat in a safe and effective manner. And so we have these exciting human results with liver and with vaccines but I see a future where we develop delivery systems for mRNA to a broad range of tissues. And this has the potential to really change how we treat many different diseases.
JOHN STERLING: So you just mentioned about these exciting results in liver and other applications. Can you talk a little bit more about those, what are these results actually showing?
DANIEL ANDERSON: Well, so I think it's not widely known that actually the first FDA-approved lipid RNA nanoparticle was for a liver genetic disease back in 2018. So this is Onpattro, it didn't deliver messenger RNA but it delivered a small RNA for RNA interference for the treatment of a disease called transthyretin-mediated amyloidosis. And in clinical trials, it actually had a really profound and helpful effect on those patients but for the field, it was really the first demonstration that these technologies are not just pie-in-the-sky ways in which we treat animals, this really is a pharmaceutical product that can help patients.
DANIEL ANDERSON: More recently, there have been examples from Intellia, where in fact by delivering a messenger RNA encoding Cas9 for the CRISPR genome editing system, they were able to permanently edit a gene in the liver, in this case, it was also this TTR gene, and provide so far, permanent therapeutic effect in these patients. More recently, they've gone on to extend this to another disease. And so it's still early but we have clear human proof that RNA therapeutics, and specifically messenger RNA, can provide human therapy in the liver.
DANIEL ANDERSON: And so to me again, there's no question in biology that messenger RNA can turn into protein inside of cells, it's really a delivery question, how do we get them into all of these different cells that we'd like to treat, and that requires advances in delivery systems.
JOHN STERLING: And that leads exactly to what you and your lab are doing. So what types of novel delivery materials has your lab been working on, and which have shown the most promise?
DANIEL ANDERSON: Well, I think probably everybody on this call has had a lipid RNA nanoparticle in their arms, and so it's hard not to argue that the lipid delivery systems are the most clinically advanced and have had the broadest impact. But how do you actually define a lipid when if you look at a chemical structure, when is a lipid, when does it become lipid-like, and when does it become something like a branched polymer or dendrimer?
DANIEL ANDERSON: We see a variety of organic molecules, whether lipids or lipid likes or even polymer systems that can provide really interesting delivery in vivo in different animal systems. And so my expectation in the near term is we're going to continue to see advances with lipid delivery systems but we may also start to see more advances with other materials like polymers. And then on top of that, there are the ligand delivery systems.
DANIEL ANDERSON: So things, for example, antibody-coated lipid nanoparticles. And there's increasing evidence in animals that these can be used to specifically deliver RNA to important cell types like immune cells or even hematopoietic stem cells.
JOHN STERLING: Well, so there really is a range of potential delivery materials?
DANIEL ANDERSON: We believe there is, yeah.
JOHN STERLING: OK. That's interesting. Nathaniel, it's been noted that self-replicating RNA may overcome the limitations of HEM RNA applications, how so?
NATHANIEL WANG: Yeah, definitely. And I think what's great about these types of panels is being able to get different perspectives. And you know, Dan was talking about some great applications on the delivery and the tissue specificity side, which I think is a very exciting part of the field. Now, we're focused on the flip side of that, which is what's actually being delivered by it. And with mRNA, what you end up getting is this quick short burst of protein that rapidly goes away.
NATHANIEL WANG: And so that's suitable for certain applications where you want, you know what I'll call for lack of a better term, hit-and-run types of proteins. These are going to be proteins where a very small amount is needed to be able to have their effect or you don't want the proteins to be hanging around in the cell for a long period of time because of the side effects it can end up causing. But that ends up walling off a large part of the therapeutic space that we would like to access in the field.
NATHANIEL WANG: So with self-replicating RNAs, you're able to get a higher amount of protein that's able to persist for a longer period of time. And that really opens up new types of proteins that you can express from it, and the types of immune responses that you can generate in terms of vaccines. And so that's one of the areas that we're particularly excited about.
NATHANIEL WANG: And that goes beyond the idea of just tissue specificity and opens up areas anywhere from oncology more, to areas like the autoimmune space, or even the metabolic space and beyond. And so those are areas that we're excited about.
JOHN STERLING: So talk a bit more about those. So you've targeted these diseases with srRNA, and what about those diseases, in particular, seemed amenable to this approach?
NATHANIEL WANG: Yeah, definitely. So you know, I'll go through those different areas one by one to give you a better sense of it. So infectious diseases we saw a huge benefit from the COVID-19 vaccines. But in a lot of ways, that was a low-hanging fruit type of target. It was an antigen or a viral protein, the spike protein that was very easy for the immune system to recognize and very easy for the immune system to target.
NATHANIEL WANG: It was also a single protein that needed to be targeted by the immune system. And so all of those things made for a profile that was really nice for an mRNA-based vaccine. And despite that, one of the things that we saw, and Dan mentioned that everybody on this call probably received RNA vaccine is-- I'm not sure about everybody else on this but I certainly got multiple doses of it.
NATHANIEL WANG: But I also had side effects each time I had it. I had those flu-like symptoms, the fever, the fatigue that lasted for days. And those are the types of side effects that can come from these types of products. What we're trying to do with self-replicating RNA is by reducing the amount of material that you need to put into a person, is theoretically you could get rid of these unwanted side effects.
NATHANIEL WANG: So by increasing the biological activity you only need a very small amount and you're able to get around the systemic side effects that people are having. It also opens up things like complex infectious diseases, things like Epstein-Barr virus, seasonal influenza cytomegalovirus, things where you need to be targeting multiple targets in the same vaccine, which is something that conventional mRNA vaccines have really been struggling with as of late.
NATHANIEL WANG: Another issue in the infectious disease space with RNA vaccines has been the lack of durability in terms of the immune responses. You're able to generate an immune response for six months, nine months, but you're not really able to get that multi-year protection you've seen with other types of technologies. And these are all things that could be potentially solved with some of the newer RNA technologies like self-replicating RNAs.
NATHANIEL WANG: If you move over into areas like cancer, a little bit further away from infectious diseases, one of the things that mRNA has not been the best at generating to date versus other types of technologies out there, has been things like T-cells. And some of these newer technologies like self-replicating RNAs, can really excel at generating T-cell responses in people.
NATHANIEL WANG: And that's particularly important when you're trying to fight off things like tumors, for which you may need certain types of T-cells called killer T-cells or helper T-cells to be able to get rid of the tumor. Then when you move even farther afield to other therapeutic areas like the autoimmune space or metabolic, you may be wanting to encode proteins that would be produced by your own cells that have certain therapeutic effects.
NATHANIEL WANG: But these types of molecules end up having very short half-lives, meaning they disappear very quickly. So an example of that is we've all heard about at this point, things like Ozempic or Wegovy or these other types of products out there but these natural versions of those products, the natural molecules produced by our bodies, may only exist on the order of minutes.
NATHANIEL WANG: And so there had to be engineering done with those types of products to extend that to hours and to days. But with these newer types of RNA technologies, you can extend those half-lives out to weeks or even to months. And so you can really see the benefits of these types of technologies when you start going into those types of therapeutic applications. So whether it's infectious disease vaccines, whether it's applications in oncology, or whether it's applications in the autoimmune, inflammation, or metabolic spaces, there's a lot of new avenues that can be opened up with these types of technologies.
JOHN STERLING: That-- boy, that is-- yeah, that is really broad. Dan, as part of the Sanofi project, you and your team are developing new lipid nanoparticle systems, you referred to before, that can be delivered in a variety of ways. So it's the system that can be delivered in a number of different techniques. What are some of these techniques and some-- does one or more work better than others?
DANIEL ANDERSON: Well, yeah. So I think we all know personally that you can get an intramuscular injection of lipid nanoparticles and get a vaccine response but it may be possible to actually have a nasal vaccine. And it's possible that nasal application could also lead to a more appropriate type of antiviral response that would, for example, provide for production of an IgA that may be helpful actually in preventing initial infection. I mean, that's just one example.
DANIEL ANDERSON: Of course, intravenous infusion is an important mode for delivering RNA to broad areas of the body but there are various local and semi-local applications that might be useful. For example, direct injection into the eye or into the back of the eye to do genome editing for certain hereditary blindness diseases. Lung inhalation through nebulization of nanoparticles into little teeny water droplets could be used to deliver messenger RNA to the epithelium of the lung and also possibly to some of the stem cell precursors to enable genome editing of the lung tissue.
DANIEL ANDERSON: So we see, of course, continued effort on examining the simple modes like intramuscular injection and IV infusion but we also see certain diseases where a more specific application could be helpful.
JOHN STERLING: Other aspects of the Sanofi project involve exploring the development of targeting molecules for use with vaccines, and also identifying strategies for enhancing vaccine effectiveness through alteration in the immunological properties of nanoparticles. Can you proffer a little more details on these two aspects of the project and what have you and your colleagues learned so far.
DANIEL ANDERSON: Yeah, so I think one goal as was mentioned, is to increase the potency without increasing the side effects. And there are a variety of strategies, actually quite a few that we're thinking about to manage this. An example is if we created a nanoparticle that was more likely to be taken up by the correct immune cells, that may allow for more specific delivery of a smaller amount of RNA and thereby reduce the potential for side effects. It may also be possible to tune the immunological properties of the nanoparticle itself.
DANIEL ANDERSON: So it's known that some of these nanoparticles can induce immune responses. And sometimes those immune responses are helpful in that they act as an adjuvant to increase the antibody production, the quality of the immune response, T-cell response. But sometimes they can also lead to some of these side effects that were mentioned, a swollen shoulder but even worse, perhaps flu-like symptoms and the fever.
DANIEL ANDERSON: And you know, nobody wants to get a flu vaccine that makes you feel like you've already had the flu. And so we see opportunities by engineering the nanoparticle itself to be more specific, to have more appropriate immunological properties, and also by engineering the RNA structure itself, either through creation of novel mRNA chemical modifications or other structures, such as self-replicating RNA.
DANIEL ANDERSON: I think there's a variety of approaches that you can use to improve the performance of these in a vaccine context and even in other settings as well.
JOHN STERLING: Yeah. It's fascinating about making them more effective and certainly cutting down on the side effects, which most of us have had to one degree or another. Nathaniel, talking about the srRNA in certain diseases, you have a pipeline of therapies, can you talk about where it stands in terms of development and what you've learned so far in these trials?
NATHANIEL WANG: Yeah, absolutely. And you know, I'll go by again each of the therapeutic areas. So one of the first areas that we're working on, which I'm sure is not surprising, is the infectious disease area. And we actually recently just initiated one of our clinical trials in this space and started to recently dose patients. And in this case, the target that we were going after was rabies.
NATHANIEL WANG: And sometimes a lot of people ask why would you go after rabies? And there's a few different reasons why it's actually one of the ideal targets to be able to assess immune responses in people. One of the first reasons is luckily, nobody's been exposed to rabies before or very few people have been exposed to it. That's in stark contrast to things like influenza or SARS-CoV-2, where if people haven't been directly vaccinated or exposed to the current circulating strains, they've certainly been exposed to related strains.
NATHANIEL WANG: And so assessing the immune response in result of vaccination can be somewhat complex. Whereas in something like rabies, it's a very clean population that you're looking at. One of the second reasons is there's WHO established correlates protection, meaning that you're able to take serum from patients, you ship them to a third-party lab which is-- then uses serum provided by the WHO to benchmark the responses in your participants.
NATHANIEL WANG: And if they're past a certain threshold they're considered to be protected against rabies. And so there's a very hard metric very early on in healthy participants to be able to determine whether this type of product is working. There's also other types of RNA-based vaccines that have been tried in the past for rabies. So you'll have some sense on how your product is actually performing.
NATHANIEL WANG: And so this is one of the reasons we were particularly interested in rabies other than, of course, the unmet need and the fact that it's a NIAID priority pathogen. And so that's something that we're pretty excited to see the results about clinically. I think that one of the things that Dan and I probably share is a true love of synthetic biology and all of these new engineering approaches that we've been using, whether it's on the particle side, whether it's on the payload or the RNA side.
NATHANIEL WANG: But ultimately it's very important to get clinical data for all of these new types of approaches because sometimes things don't perform the same in humans no matter how much testing we do in animals. And so it's important to have these well-controlled trials so that we're able to really understand how the technology is performing and ensure that it's performing in a very safe way as we do things like increase the biological activity of it, the potency of it, or the specificity of it.
NATHANIEL WANG: When we look at some of the other therapeutic areas that we're focused on such as areas like oncology, we have certain programs that are going to be ready for clinical entry in the first part of next year. And those are going to be programs that are really focused on targeting acquired resistance mutations that arise as patients are put on certain oncology agents. And it's really meant to be designed to allow patients to be on treatments that are part of early line care for a longer period of time, which is much more patient-friendly.
NATHANIEL WANG: You know, and then going to the third therapeutic area that we're really focused on in the autoimmune space, we're starting to have some very exciting results that are coming in some of the animal models that we're using, that really show the utility of the technology. And again, being able to extend the half-life of a lot of these exciting molecules that we're focused on that can really damp down the inflammation that drives autoimmune disorders.
NATHANIEL WANG: And so again across the pipeline we're starting to see a lot of programs that are either in the clinic or poised to be able to go into the clinic shortly, and the next wave of products across therapeutic areas. So it's a very exciting time for not just us, for the field. If you think of the field as something like an S-curve, we're right at the beginning of that S-curve of the field. And so we're really excited to see the exponential explosion of different types of products that are going to be developed, not just by our group but of course, by a ton of other groups out there, including Dan's and others.
JOHN STERLING: Yeah. Well, again picking up on that in clinical trials, Dan, a number of RNA delivery formulations based on your team's research are in multiple clinical trials by Sanofi for vaccine applications. Can you tell us which diseases are being targeted by those vaccines and initial results?
DANIEL ANDERSON: Yeah, I have to be careful not to speak for Sanofi and so think what I understand to be public is there's at least eight clinical trials that have happened with our formulations. And they continue to be incredibly motivated to advance technologies like this for many different diseases but I wouldn't want to comment on specific diseases or data that they generated without having their communications person know, OK, everything.
JOHN STERLING: OK, no totally understand. So I guess so a final question, Dan, I'll turn-- Nathaniel back to you in all this research-- and again so many things in science are discovered serendipitously or something just came up, weren't expected, what were some surprises that you've encountered along your way in studying mRNA vaccines in your particular approach, something you didn't expect and that's not part of your intellectual property that you didn't expect that you learned from working in this field?
NATHANIEL WANG: Yeah, definitely. So one of the things that was pretty surprising to us, although maybe it shouldn't have been in retrospect, is when we first started looking at a diversity of different vectors we thought that we were going to find some vectors that were going to be specialized for the expression of therapeutic proteins and some vectors that were going to be specialized for use in vaccines. And that's not actually what we found when we started looking at the different vectors and putting different proteins into them.
NATHANIEL WANG: What we actually found was that how the vectors performed was completely dependent on what protein they were actually expressing. And mechanistically perhaps we should have predicted this, some proteins need to be secreted into the blood to have their effect, some need to be decorated with sugars, some need to be chopped up into fragments and shown to the immune system. And these types of vectors impact the way that cells process proteins in different ways.
NATHANIEL WANG: And since every protein needs something different to be able to induce its effect, we probably should have realized that it was going to be something unique to every vector and protein combination, which is what we ultimately found. So in the end, it's not a plug-and-play technology at all. And what's actually important is that you need a diversity of vectors within your library to be able to scan through them to find the right vector for each individual protein that you want to express.
NATHANIEL WANG: And again, perhaps this is something that we should have realized because it's something we realized in the delivery space, which is you needed a diversity of chemistry to be able to scan through to find the right compositions for the right types of products. So nevertheless, that was something that was interesting and it's something that we've really started to run to ground by building these libraries of different vectors to be able to really move into these different therapeutic areas.
JOHN STERLING: Yeah. And Dan, same question for you, you're a long-term and dedicated scientist, any surprises or things that you learned you didn't expect to learn along these research paths that you've taken?
DANIEL ANDERSON: I don't think we have enough time.
JOHN STERLING: Go ahead.
DANIEL ANDERSON: Yeah. I mean, maybe just a couple examples. I mean, one early one, and this is really almost 15 years ago when we first started to look at liver delivery of RNA, in this case, it was the small interfering RNAs, was actually how many different nanoparticles worked in animals. Like I think we had the perspective that perhaps this was going to be like small molecule drug discovery, where we need to make a library of 50,000 compounds to find something that binds and has the effect but we were able to make nanoparticles several hundred and we'd find multiple that worked.
DANIEL ANDERSON: And in fact, when we moved on to primates, our lab had come up at least 10 years ago with three different chemistries that all were able to deliver RNA effectively in non-human primates, and other companies and scientists are developing them as well. And so I don't mean to make it sound easy but I guess I was surprised by how quickly we were able to find a diverse set of nanoparticles that really were able to do this in vivo.
DANIEL ANDERSON: And I think it gave the field hope that this is the kind of thing that could translate and ultimately, it did. I mean, recently the most surprising change-- and it's not really a scientific surprise but just for years we worked on these nanoparticulate RNA delivery systems, and of course, we'd have to explain what these were to anybody else that worked in science but now every time we give talks, everyone in the audience has had an RNA nanoparticle.
DANIEL ANDERSON: I've had five shots myself. And so I think the visibility of this field has really been elevated. And I think it's also encouraged people to think outside the space of vaccines and dream about a future where these particles can be used for many things, including now genome editing and permanent changes to the DNA that can be therapeutic.
DANIEL ANDERSON: And so it's really a great time to work in the field.
JOHN STERLING: Yeah. Well, Dan Anderson, Nathaniel Wang, thanks for that fascinating discussion of this very hot topic and an important topic. And you've broadened I think the knowledge of the viewers and people who are going to want to learn more about what's going on in this field. Thank you both so very much. Thank you for listening to our session. There are more sessions occurring today on the State of Biotech and hope you tune in to listen and watch.
JOHN STERLING: I'm John Sterling, Editor in Chief of GEN. Bye-bye. [MUSIC PLAYING]
Segment:0 .
[MUSIC PLAYING]
JOHN STERLING: Welcome to this GEN State of Biotech session on mRNA vaccines and therapies for cancer and other diseases. I'm John Sterling, Editor in Chief of GEN and I will be your moderator. mRNA became a huge medical topic during the COVID pandemic, turns out that mRNA has a number of other therapeutic applications as well. And that's what we'll explore with our two panelists, let's meet them.
JOHN STERLING: Dr. Nathaniel Wang is Chief Executive Officer at Replicate Bioscience and co-founder of the company. With over 15 years of leadership experience in immunology and drug development, he also is a pioneer in synthetic self-replicating RNA technologies and their delivery. Dr. Daniel Anderson is a professor of chemical engineering and a member of the Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science at MIT.
JOHN STERLING: This past April, Sanofi agreed to provide his lab with $25 million over five years to support efforts to develop next-generation delivery technology for messenger RNA. Dan also is a founder of several biopharma companies. Nathaniel, let's begin with you. What led to your interest in founding a therapeutic RNA company?
NATHANIEL WANG: Yeah, absolutely. And thanks so much for setting this up, John. So in terms of my interest, I know it's hard to remember anything before the pandemic. But people were ready to take RNA technologies behind the shed and shoot them prior to the pandemic actually happening. I think there were a lot of clinical failures in the infectious disease space that were leading up to it. And people had a lot of questions about whether the technology was going to be able to succeed, was going to be able to scale, was going to be safe in humans.
NATHANIEL WANG: And I think what the pandemic showed with a resounding yes, is that RNA technology could do all of those things. It could be scaled. It was very safe in humans, and it could be applied across a wide variety of applications. But one of the things that we realized when we were thinking about Replicate in early 2020 was that a lot of the technologies had started to stagnate, there wasn't a lot of innovation that was going on within the field as it related to some of the newer technologies like self-replicating RNAs.
NATHANIEL WANG: And we felt that one of the things that needed to be done was really to tear the technology down to the studs and rebuild it from scratch. And in doing so be able to make a lot of these engineering changes that the field had long been wanting to make in order to enable them across different therapeutic areas. And so that's what myself and some of our co-founders really struck out to do just before the pandemic hit.
JOHN STERLING: So following that line of thought, Replicate launched two years ago this month. Your stated goal was to amplify the power of mRNA therapeutics by pioneering self-replicating RNA, srRNA technology. Can you briefly describe srRNA technology and how it works?
NATHANIEL WANG: Yeah, definitely so if you think of linear mRNA, and linear mRNA is the RNA that's in the current COVID-19 vaccines, it's an instruction manual that tells a cell how to produce a protein of interest. And so you need a large amount of the synthetic material to be able to produce enough protein to induce the immune response that you want. Self-replicating RNAs in contrast, are an instruction manual that tells your cell how to produce an mRNA of interest.
NATHANIEL WANG: And so you only need a very small amount of that synthetic material. It ends up amplifying the number of fully natural mRNA copies that encode the protein that you want it to. And so you only end up needing a very small amount of synthetic material to be able to produce that therapeutic effect that you're looking for.
JOHN STERLING: So Dan, you have said that mRNA therapeutics have enormous medical potential but new delivery technology is needed to enable their broadest application. Why is this the case and what are the current limitations to mRNA therapeutic delivery?
DANIEL ANDERSON: Yeah. Well, I think as we just heard, we now have proof that mRNA can play a tremendous role as a method of creating new vaccines quickly. But perhaps less well known is there's a growing collection of human data indicating it can also be used for certain genetic diseases, for example, in the liver. mRNA as we know or were taught in our basic biology classes turns into protein in essentially all of our active cells.
DANIEL ANDERSON: And so it's really just a question of how do we deliver mRNA into cells that we want to treat in a safe and effective manner. And so we have these exciting human results with liver and with vaccines but I see a future where we develop delivery systems for mRNA to a broad range of tissues. And this has the potential to really change how we treat many different diseases.
JOHN STERLING: So you just mentioned about these exciting results in liver and other applications. Can you talk a little bit more about those, what are these results actually showing?
DANIEL ANDERSON: Well, so I think it's not widely known that actually the first FDA-approved lipid RNA nanoparticle was for a liver genetic disease back in 2018. So this is Onpattro, it didn't deliver messenger RNA but it delivered a small RNA for RNA interference for the treatment of a disease called transthyretin-mediated amyloidosis. And in clinical trials, it actually had a really profound and helpful effect on those patients but for the field, it was really the first demonstration that these technologies are not just pie-in-the-sky ways in which we treat animals, this really is a pharmaceutical product that can help patients.
DANIEL ANDERSON: More recently, there have been examples from Intellia, where in fact by delivering a messenger RNA encoding Cas9 for the CRISPR genome editing system, they were able to permanently edit a gene in the liver, in this case, it was also this TTR gene, and provide so far, permanent therapeutic effect in these patients. More recently, they've gone on to extend this to another disease. And so it's still early but we have clear human proof that RNA therapeutics, and specifically messenger RNA, can provide human therapy in the liver.
DANIEL ANDERSON: And so to me again, there's no question in biology that messenger RNA can turn into protein inside of cells, it's really a delivery question, how do we get them into all of these different cells that we'd like to treat, and that requires advances in delivery systems.
JOHN STERLING: And that leads exactly to what you and your lab are doing. So what types of novel delivery materials has your lab been working on, and which have shown the most promise?
DANIEL ANDERSON: Well, I think probably everybody on this call has had a lipid RNA nanoparticle in their arms, and so it's hard not to argue that the lipid delivery systems are the most clinically advanced and have had the broadest impact. But how do you actually define a lipid when if you look at a chemical structure, when is a lipid, when does it become lipid-like, and when does it become something like a branched polymer or dendrimer?
DANIEL ANDERSON: We see a variety of organic molecules, whether lipids or lipid likes or even polymer systems that can provide really interesting delivery in vivo in different animal systems. And so my expectation in the near term is we're going to continue to see advances with lipid delivery systems but we may also start to see more advances with other materials like polymers. And then on top of that, there are the ligand delivery systems.
DANIEL ANDERSON: So things, for example, antibody-coated lipid nanoparticles. And there's increasing evidence in animals that these can be used to specifically deliver RNA to important cell types like immune cells or even hematopoietic stem cells.
JOHN STERLING: Well, so there really is a range of potential delivery materials?
DANIEL ANDERSON: We believe there is, yeah.
JOHN STERLING: OK. That's interesting. Nathaniel, it's been noted that self-replicating RNA may overcome the limitations of HEM RNA applications, how so?
NATHANIEL WANG: Yeah, definitely. And I think what's great about these types of panels is being able to get different perspectives. And you know, Dan was talking about some great applications on the delivery and the tissue specificity side, which I think is a very exciting part of the field. Now, we're focused on the flip side of that, which is what's actually being delivered by it. And with mRNA, what you end up getting is this quick short burst of protein that rapidly goes away.
NATHANIEL WANG: And so that's suitable for certain applications where you want, you know what I'll call for lack of a better term, hit-and-run types of proteins. These are going to be proteins where a very small amount is needed to be able to have their effect or you don't want the proteins to be hanging around in the cell for a long period of time because of the side effects it can end up causing. But that ends up walling off a large part of the therapeutic space that we would like to access in the field.
NATHANIEL WANG: So with self-replicating RNAs, you're able to get a higher amount of protein that's able to persist for a longer period of time. And that really opens up new types of proteins that you can express from it, and the types of immune responses that you can generate in terms of vaccines. And so that's one of the areas that we're particularly excited about.
NATHANIEL WANG: And that goes beyond the idea of just tissue specificity and opens up areas anywhere from oncology more, to areas like the autoimmune space, or even the metabolic space and beyond. And so those are areas that we're excited about.
JOHN STERLING: So talk a bit more about those. So you've targeted these diseases with srRNA, and what about those diseases, in particular, seemed amenable to this approach?
NATHANIEL WANG: Yeah, definitely. So you know, I'll go through those different areas one by one to give you a better sense of it. So infectious diseases we saw a huge benefit from the COVID-19 vaccines. But in a lot of ways, that was a low-hanging fruit type of target. It was an antigen or a viral protein, the spike protein that was very easy for the immune system to recognize and very easy for the immune system to target.
NATHANIEL WANG: It was also a single protein that needed to be targeted by the immune system. And so all of those things made for a profile that was really nice for an mRNA-based vaccine. And despite that, one of the things that we saw, and Dan mentioned that everybody on this call probably received RNA vaccine is-- I'm not sure about everybody else on this but I certainly got multiple doses of it.
NATHANIEL WANG: But I also had side effects each time I had it. I had those flu-like symptoms, the fever, the fatigue that lasted for days. And those are the types of side effects that can come from these types of products. What we're trying to do with self-replicating RNA is by reducing the amount of material that you need to put into a person, is theoretically you could get rid of these unwanted side effects.
NATHANIEL WANG: So by increasing the biological activity you only need a very small amount and you're able to get around the systemic side effects that people are having. It also opens up things like complex infectious diseases, things like Epstein-Barr virus, seasonal influenza cytomegalovirus, things where you need to be targeting multiple targets in the same vaccine, which is something that conventional mRNA vaccines have really been struggling with as of late.
NATHANIEL WANG: Another issue in the infectious disease space with RNA vaccines has been the lack of durability in terms of the immune responses. You're able to generate an immune response for six months, nine months, but you're not really able to get that multi-year protection you've seen with other types of technologies. And these are all things that could be potentially solved with some of the newer RNA technologies like self-replicating RNAs.
NATHANIEL WANG: If you move over into areas like cancer, a little bit further away from infectious diseases, one of the things that mRNA has not been the best at generating to date versus other types of technologies out there, has been things like T-cells. And some of these newer technologies like self-replicating RNAs, can really excel at generating T-cell responses in people.
NATHANIEL WANG: And that's particularly important when you're trying to fight off things like tumors, for which you may need certain types of T-cells called killer T-cells or helper T-cells to be able to get rid of the tumor. Then when you move even farther afield to other therapeutic areas like the autoimmune space or metabolic, you may be wanting to encode proteins that would be produced by your own cells that have certain therapeutic effects.
NATHANIEL WANG: But these types of molecules end up having very short half-lives, meaning they disappear very quickly. So an example of that is we've all heard about at this point, things like Ozempic or Wegovy or these other types of products out there but these natural versions of those products, the natural molecules produced by our bodies, may only exist on the order of minutes.
NATHANIEL WANG: And so there had to be engineering done with those types of products to extend that to hours and to days. But with these newer types of RNA technologies, you can extend those half-lives out to weeks or even to months. And so you can really see the benefits of these types of technologies when you start going into those types of therapeutic applications. So whether it's infectious disease vaccines, whether it's applications in oncology, or whether it's applications in the autoimmune, inflammation, or metabolic spaces, there's a lot of new avenues that can be opened up with these types of technologies.
JOHN STERLING: That-- boy, that is-- yeah, that is really broad. Dan, as part of the Sanofi project, you and your team are developing new lipid nanoparticle systems, you referred to before, that can be delivered in a variety of ways. So it's the system that can be delivered in a number of different techniques. What are some of these techniques and some-- does one or more work better than others?
DANIEL ANDERSON: Well, yeah. So I think we all know personally that you can get an intramuscular injection of lipid nanoparticles and get a vaccine response but it may be possible to actually have a nasal vaccine. And it's possible that nasal application could also lead to a more appropriate type of antiviral response that would, for example, provide for production of an IgA that may be helpful actually in preventing initial infection. I mean, that's just one example.
DANIEL ANDERSON: Of course, intravenous infusion is an important mode for delivering RNA to broad areas of the body but there are various local and semi-local applications that might be useful. For example, direct injection into the eye or into the back of the eye to do genome editing for certain hereditary blindness diseases. Lung inhalation through nebulization of nanoparticles into little teeny water droplets could be used to deliver messenger RNA to the epithelium of the lung and also possibly to some of the stem cell precursors to enable genome editing of the lung tissue.
DANIEL ANDERSON: So we see, of course, continued effort on examining the simple modes like intramuscular injection and IV infusion but we also see certain diseases where a more specific application could be helpful.
JOHN STERLING: Other aspects of the Sanofi project involve exploring the development of targeting molecules for use with vaccines, and also identifying strategies for enhancing vaccine effectiveness through alteration in the immunological properties of nanoparticles. Can you proffer a little more details on these two aspects of the project and what have you and your colleagues learned so far.
DANIEL ANDERSON: Yeah, so I think one goal as was mentioned, is to increase the potency without increasing the side effects. And there are a variety of strategies, actually quite a few that we're thinking about to manage this. An example is if we created a nanoparticle that was more likely to be taken up by the correct immune cells, that may allow for more specific delivery of a smaller amount of RNA and thereby reduce the potential for side effects. It may also be possible to tune the immunological properties of the nanoparticle itself.
DANIEL ANDERSON: So it's known that some of these nanoparticles can induce immune responses. And sometimes those immune responses are helpful in that they act as an adjuvant to increase the antibody production, the quality of the immune response, T-cell response. But sometimes they can also lead to some of these side effects that were mentioned, a swollen shoulder but even worse, perhaps flu-like symptoms and the fever.
DANIEL ANDERSON: And you know, nobody wants to get a flu vaccine that makes you feel like you've already had the flu. And so we see opportunities by engineering the nanoparticle itself to be more specific, to have more appropriate immunological properties, and also by engineering the RNA structure itself, either through creation of novel mRNA chemical modifications or other structures, such as self-replicating RNA.
DANIEL ANDERSON: I think there's a variety of approaches that you can use to improve the performance of these in a vaccine context and even in other settings as well.
JOHN STERLING: Yeah. It's fascinating about making them more effective and certainly cutting down on the side effects, which most of us have had to one degree or another. Nathaniel, talking about the srRNA in certain diseases, you have a pipeline of therapies, can you talk about where it stands in terms of development and what you've learned so far in these trials?
NATHANIEL WANG: Yeah, absolutely. And you know, I'll go by again each of the therapeutic areas. So one of the first areas that we're working on, which I'm sure is not surprising, is the infectious disease area. And we actually recently just initiated one of our clinical trials in this space and started to recently dose patients. And in this case, the target that we were going after was rabies.
NATHANIEL WANG: And sometimes a lot of people ask why would you go after rabies? And there's a few different reasons why it's actually one of the ideal targets to be able to assess immune responses in people. One of the first reasons is luckily, nobody's been exposed to rabies before or very few people have been exposed to it. That's in stark contrast to things like influenza or SARS-CoV-2, where if people haven't been directly vaccinated or exposed to the current circulating strains, they've certainly been exposed to related strains.
NATHANIEL WANG: And so assessing the immune response in result of vaccination can be somewhat complex. Whereas in something like rabies, it's a very clean population that you're looking at. One of the second reasons is there's WHO established correlates protection, meaning that you're able to take serum from patients, you ship them to a third-party lab which is-- then uses serum provided by the WHO to benchmark the responses in your participants.
NATHANIEL WANG: And if they're past a certain threshold they're considered to be protected against rabies. And so there's a very hard metric very early on in healthy participants to be able to determine whether this type of product is working. There's also other types of RNA-based vaccines that have been tried in the past for rabies. So you'll have some sense on how your product is actually performing.
NATHANIEL WANG: And so this is one of the reasons we were particularly interested in rabies other than, of course, the unmet need and the fact that it's a NIAID priority pathogen. And so that's something that we're pretty excited to see the results about clinically. I think that one of the things that Dan and I probably share is a true love of synthetic biology and all of these new engineering approaches that we've been using, whether it's on the particle side, whether it's on the payload or the RNA side.
NATHANIEL WANG: But ultimately it's very important to get clinical data for all of these new types of approaches because sometimes things don't perform the same in humans no matter how much testing we do in animals. And so it's important to have these well-controlled trials so that we're able to really understand how the technology is performing and ensure that it's performing in a very safe way as we do things like increase the biological activity of it, the potency of it, or the specificity of it.
NATHANIEL WANG: When we look at some of the other therapeutic areas that we're focused on such as areas like oncology, we have certain programs that are going to be ready for clinical entry in the first part of next year. And those are going to be programs that are really focused on targeting acquired resistance mutations that arise as patients are put on certain oncology agents. And it's really meant to be designed to allow patients to be on treatments that are part of early line care for a longer period of time, which is much more patient-friendly.
NATHANIEL WANG: You know, and then going to the third therapeutic area that we're really focused on in the autoimmune space, we're starting to have some very exciting results that are coming in some of the animal models that we're using, that really show the utility of the technology. And again, being able to extend the half-life of a lot of these exciting molecules that we're focused on that can really damp down the inflammation that drives autoimmune disorders.
NATHANIEL WANG: And so again across the pipeline we're starting to see a lot of programs that are either in the clinic or poised to be able to go into the clinic shortly, and the next wave of products across therapeutic areas. So it's a very exciting time for not just us, for the field. If you think of the field as something like an S-curve, we're right at the beginning of that S-curve of the field. And so we're really excited to see the exponential explosion of different types of products that are going to be developed, not just by our group but of course, by a ton of other groups out there, including Dan's and others.
JOHN STERLING: Yeah. Well, again picking up on that in clinical trials, Dan, a number of RNA delivery formulations based on your team's research are in multiple clinical trials by Sanofi for vaccine applications. Can you tell us which diseases are being targeted by those vaccines and initial results?
DANIEL ANDERSON: Yeah, I have to be careful not to speak for Sanofi and so think what I understand to be public is there's at least eight clinical trials that have happened with our formulations. And they continue to be incredibly motivated to advance technologies like this for many different diseases but I wouldn't want to comment on specific diseases or data that they generated without having their communications person know, OK, everything.
JOHN STERLING: OK, no totally understand. So I guess so a final question, Dan, I'll turn-- Nathaniel back to you in all this research-- and again so many things in science are discovered serendipitously or something just came up, weren't expected, what were some surprises that you've encountered along your way in studying mRNA vaccines in your particular approach, something you didn't expect and that's not part of your intellectual property that you didn't expect that you learned from working in this field?
NATHANIEL WANG: Yeah, definitely. So one of the things that was pretty surprising to us, although maybe it shouldn't have been in retrospect, is when we first started looking at a diversity of different vectors we thought that we were going to find some vectors that were going to be specialized for the expression of therapeutic proteins and some vectors that were going to be specialized for use in vaccines. And that's not actually what we found when we started looking at the different vectors and putting different proteins into them.
NATHANIEL WANG: What we actually found was that how the vectors performed was completely dependent on what protein they were actually expressing. And mechanistically perhaps we should have predicted this, some proteins need to be secreted into the blood to have their effect, some need to be decorated with sugars, some need to be chopped up into fragments and shown to the immune system. And these types of vectors impact the way that cells process proteins in different ways.
NATHANIEL WANG: And since every protein needs something different to be able to induce its effect, we probably should have realized that it was going to be something unique to every vector and protein combination, which is what we ultimately found. So in the end, it's not a plug-and-play technology at all. And what's actually important is that you need a diversity of vectors within your library to be able to scan through them to find the right vector for each individual protein that you want to express.
NATHANIEL WANG: And again, perhaps this is something that we should have realized because it's something we realized in the delivery space, which is you needed a diversity of chemistry to be able to scan through to find the right compositions for the right types of products. So nevertheless, that was something that was interesting and it's something that we've really started to run to ground by building these libraries of different vectors to be able to really move into these different therapeutic areas.
JOHN STERLING: Yeah. And Dan, same question for you, you're a long-term and dedicated scientist, any surprises or things that you learned you didn't expect to learn along these research paths that you've taken?
DANIEL ANDERSON: I don't think we have enough time.
JOHN STERLING: Go ahead.
DANIEL ANDERSON: Yeah. I mean, maybe just a couple examples. I mean, one early one, and this is really almost 15 years ago when we first started to look at liver delivery of RNA, in this case, it was the small interfering RNAs, was actually how many different nanoparticles worked in animals. Like I think we had the perspective that perhaps this was going to be like small molecule drug discovery, where we need to make a library of 50,000 compounds to find something that binds and has the effect but we were able to make nanoparticles several hundred and we'd find multiple that worked.
DANIEL ANDERSON: And in fact, when we moved on to primates, our lab had come up at least 10 years ago with three different chemistries that all were able to deliver RNA effectively in non-human primates, and other companies and scientists are developing them as well. And so I don't mean to make it sound easy but I guess I was surprised by how quickly we were able to find a diverse set of nanoparticles that really were able to do this in vivo.
DANIEL ANDERSON: And I think it gave the field hope that this is the kind of thing that could translate and ultimately, it did. I mean, recently the most surprising change-- and it's not really a scientific surprise but just for years we worked on these nanoparticulate RNA delivery systems, and of course, we'd have to explain what these were to anybody else that worked in science but now every time we give talks, everyone in the audience has had an RNA nanoparticle.
DANIEL ANDERSON: I've had five shots myself. And so I think the visibility of this field has really been elevated. And I think it's also encouraged people to think outside the space of vaccines and dream about a future where these particles can be used for many things, including now genome editing and permanent changes to the DNA that can be therapeutic.
DANIEL ANDERSON: And so it's really a great time to work in the field.
JOHN STERLING: Yeah. Well, Dan Anderson, Nathaniel Wang, thanks for that fascinating discussion of this very hot topic and an important topic. And you've broadened I think the knowledge of the viewers and people who are going to want to learn more about what's going on in this field. Thank you both so very much. Thank you for listening to our session. There are more sessions occurring today on the State of Biotech and hope you tune in to listen and watch.
JOHN STERLING: I'm John Sterling, Editor in Chief of GEN. Bye-bye. [MUSIC PLAYING]
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