Welcome everyone to the Global Healthcare Conference of Leerink Partners for 2026. I'm Lili Nsongo, and I'm joined today by Josh Mandel-Brehm, the CEO of CAMP4. Josh, welcome. Great. Thank you for having us here. Well, thanks for coming. Maybe we can just dive right in. I'm just gonna give you some time so you can give us an overview of your technology platform, given how differentiated it is from most of the approaches that we encounter. Yep, absolutely. Maybe I'll just start with the simple tagline. We use antisense oligonucleotides to increase gene expression. You can think about us as the inverse of most of the oligo companies in terms of downregulation. The way that we are able to do this is by targeting a new category of RNAs called regulatory RNAs. These are RNAs that come out of the non-coding genome, specifically enhancers and promoters. What we've discovered through one of our founders, Richard Young, as well as at CAMP4, is that every protein coding gene in the human body relies on its own unique set of regulatory RNAs to control gene expression. We've effectively put together a platform that first and foremost allows us to catalog all of the regulatory RNAs and the genes that they correspond to in any given cell type. Then we've figured out how to selectively drug a regulatory RNA using a standard chemistry ASO to allow us to increase gene expression. I'd say one of the unique features that differentiates it from sort of the classic, RNAs or steric, oligos that target mRNA, is that by targeting these regulatory RNAs, we can get a very precise upregulation. Unlike microRNAs or long non-coding RNAs that are pleiotropic, this is very specific to the gene region and very controlled as well, but it has very different types of biology, very different kinetics. That's a lot of what our platform is doing, is basically learning that whole new area of biology using ASO chemistry. Maybe on the fundamental science side of things. Obviously, when we think about ASO or siRNA, we think about gene silencing and- Yeah. ... for most indications, the more silencing you have, the more knock down to knock out you have- Yeah. ...the better, right? Right. That's the goal. How should we think about that in terms of overexpression? Is there a sweet spot you're trying to reach? Yeah. ... the indication, or are you going after indications where the more is the better? Yeah, no, it's a very good question. To just answer it right from the get-go, there is a sweet spot, at least for the diseases we're focused on, which are haploinsufficient. Mathematically, you are missing 50% of what you need to otherwise be healthy. The sweet spot then is a twofold increase. Interestingly, that's exactly where this biology takes you. What we have found, and we've tested this in over 40 different target genes actually, is that when you do what I just said, so you target a regulatory RNA with an antisense oligonucleotide in vivo, you get about a twofold increase. Interestingly, the cell doesn't want you to go above that. It governs itself, probably because of toxicity and other cellular mechanisms. There are hundreds of different haploinsufficiencies. Most of them have no approved treatments, it allows us to basically take the technology there. We get asked from time to time, "Are you worried about that?" That's not something we're concerned with. It tends to hover right around 2-fold, so it's sort of the ideal target space for us to be able to use that technology. You know, interestingly, the one thing that I think is unique about the upregulation field is, you alluded to this, when you're downregulating things, you're used to seeing curves where you're showing a 90%, 95% decrease, it's very clear to see. Upregulation is a very different field, when you're dealing with changes that are anywhere from 1.5 to 2-fold, which is 100%, but effectively you have to be able to see the signal through the noise. We've had many different assays that we've developed and ways of effectively being able to look at the biology and say, "Okay, that's real. That's an actual increase versus something that's noise." I think that's one of the sort of most important parts of this new field, is that you're just dealing with a whole new way of looking at the biology. Haploinsufficient indication, you're able to double the expression or bring it to a level that's closer to what you would see in the wild type. Mm-hmm. Now, with the approach, how should we think about durability when we compare it to, say, you know, traditional ASOs and RNAs? Yeah, I mean, you know, interestingly, to start with, we're using the same state-of-the-art chemistry that's in approved drugs like SPINRAZA for SMA. We're, you know... Part of our strategy is to buy down as much risk as we can and not take on things where we, you know, we can't solve that risk. Using chemistries that are known to us, well understood is one area where we do that. It turns out and by doing that, obviously, you can look at decades of research and clinical studies and compare and contrast. The short answer is the pharmacokinetics and the pharmacodynamics. When we look at the pharmacokinetics specifically, it tends to overlay pretty nicely on what you see actually for other ASOs. What that ultimately means is that we think the dosing should be similar to what you'd see for your standard ASO chemistry. That's the good news, is that you get the advantage that we all like with oligos and siRNA, which is sort of longer lasting dosing. Great. Now that we've had an overview of the platform, diving into the program. Obviously, you have shifted, you know, from the urea cycle disorder program to prioritizing the SYNGAP1 program. Before we dive into the SYNGAP1 program, I wanted to ask if you could walk us through the rationale of the reprioritization, and then any learnings from the UCD program that applies to your understanding of your own platform and as well as, you know, read through to the SYNGAP1 program. Yeah. As I was walking over here with my CFO, I was like, "How do I tell people that I like one child more than the other and do it politely?" You know, a couple things. One is I think, so we are a platform company, but actually what I like to tell people is we are a product company with a platform, and in order to get to that point in time, you really need to, I think, find religion with where your technology works best and also make sure that fits within what the company's capable of doing. You know, last year was a year where many companies had to do a lot of thoughtful reprioritization given budget constraints, high cost of capital, et cetera, and we're no different than that. That's one feature of it. The other is that actually just the SYNGAP1 program in and of itself, the preclinical data gives us high conviction that it should be successful in the clinic, and we can talk more about that. It is a massive unmet need. There's no approved treatments there, and it's a relatively large rare disease. We looked at that and we said, "Okay, this is a very compelling opportunity for CAMP4." Behind that, there are other, and we'll talk about this, I know, SYNGAP1-like opportunities. Mm-hmm. We looked at that and we said, "Okay, this is something where it can be, for example, to use an analogy, TTR program that we can build from but in the CNS," right? We saw that we could build an entire pipeline there. Our urea cycle program is a very clever approach. It's also a very high unmet need. It is a smaller market, but still a market nonetheless, and it's not a haploinsufficiency, right? I told you before, we've found that our technology's really well suited for haploinsufficiencies, but I think more importantly, in the liver, we didn't necessarily see a franchise beyond UCD for us to build a pipeline from at CAMP4. It was on its own. From that perspective, we can only take on so many programs, and we decided for those reasons to shift to SYNGAP1. What we learned from the urea cycle program is a few really important pieces of information. The first is the pharmacokinetics, so we know that targeting now regRNAs, it seems to be similar to other oligos in terms of what you'd expect. It was very safe, so we had no safety issues whatsoever. Lastly, as a small company, it was our first time going into the clinic, and I'd say we executed to perfection. Everything was done on time. We did it ex-US, in Australia. We just opened a CTA in Europe for that program as well. That actually has a lot of read-through to other programs coming down the pipeline, in particular for working with regulatory agencies and how we progress, for example, the SYNGAP1 program. Last question on the urea cycle disorder program? As you mentioned, it was a well-designed, well-executed program clinically. How are the potential partnership discussions evolving? We just kicked those off in the beginning of the year, and just getting going. What I'd say is that there's definitely people I think very interested in the program itself. They're following along with it. I think it's more of just a question of finding the right home for somebody who has a franchise that fits in those rare diseases and urea cycle. We're in those discussions now, and we're hoping that we can give that a home, that somebody else can progress it forward. Great. Now shifting to the favorite child, the SYNGAP1 program. Yeah. Can you provide us an overview of the indication and the current management? Absolutely. I mentioned this before. SYNGAP1 is a bona fide haploinsufficient disease. Effectively, one of your alleles no longer makes a healthy protein, that means you essentially make 50% of what you otherwise need to be healthy. These patients have no disease-modifying therapies available to them. In fact, they have almost no therapies available to them. They range from it obviously affects children, but these children become adults, and then they get institutionalized, so it's a lifelong disease. The hallmarks of the disease are, first and foremost, you have a learning disability, cognitive impairment, seizures. These kids can have 10, 20 seizures a day. They can't sleep. They have mobility issues. In fact, if you were to go to any of the Cure SYNGAP1 Foundation events where many families come in, what you'd find is all of the parents have the tattoo, which is essentially bite marks up and down their arms 'cause these kids can't communicate well, and so they're so frustrated with their situation. It is a really terrible disease. Really importantly, it is not a neurodegenerative disease. It is a neuroarrest disease, meaning that we think these kids are just stuck in their bodies, and that effectively, if you can go to the underlying cause of the disease, that you should be able to actually ameliorate these symptoms and actually help them live a much better life. You mentioned something very important. You, you think those patients are kind of stuck and there's a need for, like, an unlocking- Yeah ...that could potentially lead to great improvements. I, that's a very selfish question because I've been doing a lot of kind of research on SYNGAP1. Yeah. It seems like there hasn't been a consensus in terms of the window of time within which you can have the most impact with a therapy. Yeah. What is your opinion of that? Do you think we've reached kind of an understanding of how far can you go before you have done something irreversible or before plasticity is just set and you can't really? Yeah improve over? I don't think we're anywhere near understanding whether or not and when, to your point. I think until we have a therapeutic to test, we won't really know the answer. Also, I think you hit it on the head, the research, like, interestingly, the people first say, "Well, how come I haven't heard of this," right? You get very intrigued by the biology, and actually, if you look at the publications from when the gene was discovered in 2009 to, I mean, you've hundreds of publications now about this, so it's very well studied, to your point. Interestingly, a couple things I'll point out. One is at least preclinically, for example, in our own data, we showed that we could reverse the symptoms of the disease in terms of anxiety and other sort of related phenotypes in a humanized mouse model. Others have done work in older mice and shown that they can reverse the disease as well. I think preclinically, everybody's done as much as they can do given the models available to show reversibility. That's one piece. Interestingly, I was talking to the head of the foundation, he was saying, you know, as kids progress to adults and get older in life, they actually continue to develop new symptoms, which at least in his mind says this disease doesn't just stabilize, it just keeps getting worse, and other new things come about. Even if you're older and you can't necessarily reverse some things, there are still other things that I think actually are really important and can actually keep people from being institutionalized or other issues that are a high cost on the families and the patients themselves. I think there's a lot of hope to believe that at different stages of life, actually if you have a therapeutic that deals with the underlying cause of the disease, that you should be able to have a meaningful impact. With all that said, like any other rare, devastating disease, the trick is to get in there as early as possible before any damage is done, and that's our intention as well. What does that mean, as early as possible? When we think about potential clinical development. Right ... what would be your target or your ideal target population, in terms of age range? Yeah Characteristics as well? At present, and this is a good thing, it used to be very different, but what ends up happening... Let me start with diagnosis, 'cause that's actually important. Typically what happens is these children miss a development milestone, a neurodevelopment milestone, as a parent you can figure that out, or they have seizures. It used to be a diagnostic odyssey, but now with whole genome sequencing, whole exome sequencing, and genetic panels that have SYNGAP1 on it, you immediately get that genetic diagnosis. That's still about age 2 or 3. For practical purposes, that's kind of as early as you're gonna go. Right now, I think that'll change and is changing over time for a lot of different reasons, but, you know, our intention is to get down to treat, at least in our first clinical study, as young as 2 or 3 years old, let's say. Those are the conversations we're having with regulatory agencies, and that's really the target population to start with is sort of the, you know, we'll say 2 to 18, but to get as young as possible in that case. So one thing that you mentioned is the presentation can vary. It could be seizures, it could be missing some of the milestones. Do you see that heterogeneity as potentially delineating a smaller population that you might target first, or do you intend on just taking any type of clinical presentation? Just to give context to that, I think about this disease in sort of three buckets. 80% of patients have truncating mutations, which means they are extremely homogeneous. Those patients, 97% of them tend to have a very high seizure rate, for example. They tend to be very sick, they can't speak, et cetera. There's another 15%-18% that have missense mutations that are also very, very sick, a little more heterogeneous. Actually you have 1%-2% of patients that have a milder mutation that give about 75% levels of SYNGAP1. Actually you know that they can speak, they can go to special schools, they can respond a little bit to some medicines. That also tells us that there's a threshold where you get to where you can start to shift this population. That's useful for us. We're gonna start in that 80% population, and as you pointed out, we'll try and go as young as possible. We will set certain thresholds for seizures and whatnot to try and get it as homogeneous as possible. That'll still, I think, give way to the, at least to start with, 80% of the population. We're starting there. Okay. We touched upon the target population for clinical development. As we think about the clinical program, usually in clinical development we get SAD and then we get MAD, but you had mentioned, you know, intention of getting MAD right away. Can you- That sounds fun. Right? No, no sadness. Yeah. Just to the madness right away. Yeah. You know. Yeah ... can you kind of walk us through the rationale? Yeah ... for going directly in multiple ascending dose, and also what the regulatory feedback has been for that? Couple things. We've benchmarked a lot in recently, meaning looking at all the other companies that have come before us using CNS approaches, using oligos. It turns out that actually this is not a novel concept, that there are multiple examples of companies that are going right into a MAD study. What's the reason for that? If you have a disease with an extremely high unmet need, and you have a product profile that I think the regulatory agencies are comfortable with... By the way, they're getting more and more and more comfortable with oligos in the CNS- Mm-hmm ... because, you know, seven, eight years ago, maybe even longer, we started with SPINRAZA, right? Now you've had so many things come through that I actually think, you know, we've been very reassured. We haven't talked too publicly about this, but we are having many different conversations with the regulatory agencies, and I have to say it's very reassuring that actually they've come and said, "We're comfortable with this. We've seen that. We know this." Like, they're actually telling us what they know. I think what it comes down to is ethical, where they're like, okay, I'm just paraphrasing now, but if you have something that can help a very sick population, we wanna make sure we can get you as close as possible to the therapeutic dose to start with, and time is your enemy, right? We wanna make sure. Giving a single dose of an intrathecally delivered oligo that's not really gonna help anybody. Some could consider that unethical, and I do think that regulatory agencies acknowledge that. Yeah. I think that's what's behind it. It's more of a balance between what matters more, safety or sort of doing an invasive procedure, if you will, that may not help somebody. You'd mentioned that you've been benchmarking a lot. With that in mind, can you give us an overview of what is available in terms of natural history? Yeah ... and how could that be used, during clinical development? Even though this disease is a recent one, if you will, and I should say, you know, for those out there, every three to five years, a rare disease gets discovered that nobody's ever heard of and then becomes the next CF, SMA, et cetera. I think this is that. I think the CURE SYNGAP1 Foundation deserves a lot of credit. They are operating in a very sophisticated and smart way. You need that in these types of diseases. As a result of that, they're not only preclinical models, but they've actually invested in natural history studies, and there's one in Europe, there's one in the U.S., there's actually Quite a few happening. Collectively, there's about 1,300 patient years, which is pretty good. The majority of it is in the younger patients, which is fine, not the older. We'd wanna get there. We've been actually working with them to add additional endpoints for them to be studying as well. What I can tell you right now is, it's a robust data set, and it's helping to inform the design of our Phase 1/2. I don't think it's quite at the point where you could use it as in control, but that's okay. That's, like, where we come in, and we're starting to collaborate with them and set that up so that it's actually the right data set so that it becomes a tool for regulatory agencies and what have you. Both matures at the same time. Absolutely ... in conversions. I gotta say, you know, Penn and CHOP are doing a terrific job, and again, the data they have so far has actually already helped us in thinking about our inclusion/exclusion criteria, back to the question you've asked, which is, what's the right population to study this in? We have really good data there. Maybe going a little further ahead, how should we think about, well, one, endpoints that matter for that? Yeah ... patient population, and 2, potential pivotal endpoints? Yep. Two really important things we think a lot about, which is, like, we wanna show our drug works, we wanna show it's safe, and we wanna make sure we find the right optimal biological dose. We also wanna get this thing to market as quickly as possible for clear reasons. Because we are the first ones bringing a drug into the clinic for SYNGAP1 that is disease modifying, we have a real opportunity, but we're also blazing a path. We don't have anything to compare against yet. Yeah. Right? We're studying many, many things, ranging from seizures, which many people know is a provable endpoint, and we're gonna use video EEGs and home EEGs, to sleep scores, to Vineland, to Bayley, because as I mentioned, they have mobility issues and other neurocognitive issues. You know, we can look to other diseases as surrogates here. We can look at what they've done, companies have done with Rett syndrome. We can look at what's been done with Dravet, and we can pull that in as well. That's all been very, very useful for us and essentially our plan is to bring that all into the study, if you will, and use that to collect many different types of data. Look, we are trying to set up the study to be the most robust way of doing it in the sense that if we have the type of result that gets us those three success criteria, that we can have the right discussions with regulatory agencies about how quickly can we move forward, and what does that look like? Whether that's accelerated versus a traditional registrational study, we're trying to be very thoughtful, and that includes thinking about a control as well. Maybe can you give us an overview of the key preclinical data that you have so far that are kind of influencing how you think about clinical development? Yeah. What I can say is from cells in a dish, including patient-derived iPSC cells from SYNGAP1 patients, all the way through humanized mice that represent the disease to primates, using our human development candidate, we have shown that it can increase mRNA, increase protein, as well as reverse symptoms of the disease. In the patient-derived cells, we showed we could restore it back to the healthy state. In the humanized mice, I'd say there's two really important things that we showed, and I say humanized because we actually took the regulatory regions that have the RNAs from the human brain into the mice, so it allowed us to use our human candidate. One is it showed us that we could reverse symptoms across multiple metrics of the disease, and I believe we were the first and only ones to do that, which was, you know, very, very exciting, if you will. I think the other part of it is it allowed us to then go into primates where that's the clinical route of administration. What I can say is when you're using oligos or siRNA against monogenic diseases, so single gene diseases, and you show a pharmacodynamic marker in primates, that tends to translate well into the clinic. Mm. That's no guarantee of success, but that gives us a ton of confidence, both in terms of showing that we could increase twofold. That's what we also showed in the mice, that when we looked at the protein, it was a twofold increase, which is a subtle but important point. In haploinsufficient states, when we use our technology, we tend to get about a twofold increase. In a wild type state, like the primates, we get about a 1.5 to 1.7. Again, that goes back to your question of, are you gonna overexpress? We think the system doesn't want overexpression, but the fact that we could increase about 50% to 75% in normal, healthy primates I think was very impressive, and there were no side effects in those primates either. Yeah. We believe in a haploinsufficient state, we should be able to restore back to twofold. Thinking about the learnings from preclinical and then the translation into the clinic, you had mentioned that in terms of pharmacodynamic, what you've learned so far is that the platform, you know, we can think about it as quite similar to what we've seen with ASOs. Mm-hmm. How should we think about dosing schedule? The reason I'm asking is because in the world of ASO and RNAi, what we are seeing is next generation assets that are leading to more flexibility in dosing schedule, kind of like longer intervals... Yep between doses. How should we think about initial dosing schedule as the program moves to the clinic? Yeah. We think a lot about that too. I mean, we're already thinking about lifecycle management- Mm ... for the reasons you pointed out. Right now, given the PK characteristics, and we've shown some of this in primates, and, we expect it would be similar to what you would have seen in SPINRAZA or other drugs, which is you do a dose loading maybe once per month for three or four months, where you get to a standing concentration of oligos. Oligos tend to have a long half-life, three to six months, and then you spread that dosing every quarterly or every two quarters. Now, we won't know until we get into the clinic and start doing that, but at least the data today suggests that it should be no different than other oligos. Mm-hmm. That's our intention as far as we go. you know, in terms of longer lasting. It's interesting, we get asked a lot about shuttle technology and, you know, that's all interesting. I'm more intrigued by, for example, what Ionis and Biogen are doing with the SPINRAZA 2.0, which is once a year- Yeah ... intrathecal, which I think's pretty good. We're looking at that stuff as well. I think the patients agree. Yeah. Yeah, I mean, you know, look, intrathecal sounds invasive, but many, many places around the world can do it. It's not something that intimidates them. It's actually they know how to do it, they do it well. For patients too, in these diseases, they readily accept it. I think the more you can dose it, spread it out, actually, the more. By the way, you're putting it directly into the brain. Yeah. Like, there's an advantage to that as well. You're not putting it in the rest of the body, too. There's some advantages. As we move toward the clinic, can you maybe give us a sense of what are the key remaining steps before the program is in the clinic, it's all set, and, you know, off to pivotal? Yeah, yeah. What we've said publicly, and we said this at the end of last year, is we have our GLP toxicology studies ongoing. Everybody can do math and knows that should be wrapping up shortly. We're happy with the progress. What else needs to happen? Manufacturing, we're happy with the progress. You asked about this earlier, we haven't said publicly, but obviously before you go and you submit CTAs, INDs, et cetera, you have conversations with the regulatory agencies. Those have been ongoing as well. I'd say it's completing our toxicology studies, completing manufacturing, having ongoing discussions with regulatory agencies to basically make sure we're aligned before we submit those applications. That's all been progressing steadily. Team is heads down and, you know, we are, I would say, as I alluded to, finding that surprisingly, but in a great way, these regulatory agencies are very familiar with these technologies and it's really reassuring to hear that. Great. We look forward to the program advancing to the clinic. I also wanted to take a few minutes to talk about the GSK collaboration. Mm-hmm. Maybe can you give us an overview, but also how should we think about the cadence of potential milestones? Going way back to the beginning, what I just told you was that we use oligos to increase genes, and theoretically, you should be able to do that in any tissue type where you have a specific gene that you want to increase about twofold, and there are both rare and non-rare diseases that fall in that category. Now, we've chosen to build our own pipeline in the CNS, and we can talk a little bit more about what the future looks like there. There are other tissues where there's lots of good ideas, and we have companies coming to talk to us about that. GSK is no different. They had two large diseases in mind, one in the CNS and one in the kidney. Effectively, they believed they had delivery technology for the kidney as well. They came to Camp Four and said, "These are the genes that are underlying these diseases." We're responsible for identifying the regulatory RNA and creating the ASO leads to essentially hand over for them to make products and move forward. Right now, the ball's in our court, so to speak, to do what I just said, which is, map out those genes, catalog where the regulatory RNAs are, create the oligos, and then, in the future, we get milestones as they start to progress, if you will, those oligos towards the clinic. It's probably a little too early for us to say that, to give clarity on, if you will, the milestones, but I would say probably not until 2027 is when we'll start seeing it, more milestones. They give us a very rich upfront, $70 and a half million to cover that work, and so we're quite happy with that. Okay. How should we think, you know, you've mentioned that there are specific type of indications that are great for the platform. Yeah. How should we think about the partnered indications versus the internal indications? How would you pick one over the other? Yeah. We, we have this actually worked out and, you know, that's the advantage of basically behind the scenes doing this over the last 7 years. We know essentially. Simply said, there are 4 or 5 other ideas we have that are SYNGAP1-like opportunities. What do I mean by that? They're in the brain, they're in the same regions where we know we can get oligo. They have significant unmet needs. There's no approved treatments for them. They're haploinsufficiencies, so they speak to that 2-fold. We think we could be the first in the clinic for multiple of them. What I can tell you is we're already working on 3 DEEs, developmental and epileptic encephalopathies. They all fall in that category. We have some early promising data on those. We said publicly we're gonna announce at least one of them this year and start letting people know. We're just being quiet about it. We're holding tightly to those because we think. Oh, by the way, same KOLs, same call points, same academic collaborators. We see it as a multi-billion dollar franchise. I mean, we think it could be huge for CAMP4, and we think that actually we can own those things. We're being very selfish about that. We've had multiple companies come talk to us about those, and we've just said it's just we're gonna hold on to those right now. We don't feel the need to own too much else outside of that right now. Those larger diseases or I would say things that necessarily you might have a lot of conviction in the gene to increase, but it's not a haploinsufficiency, for example, we're not gonna do those right now. If there's other tissues, we're gonna put those in the BD bucket too. Great. It seems like a very disciplined approach that may lead to a kind of like a lot of congruence or overlap between programs so that it's a franchise that's pretty centralized in terms of the expertise that you might need, but also the physicians that you might encounter down the road in the commercial space. Yeah. I mean, I think we have Look, we have a rare opportunity, no pun intended, where if we show, when we show our SYNGAP1 program works, first of all, that is a multi-billion dollar opportunity, right? We think it's a big, big opportunity. Because it reads through to the People always ask, "Does it read through?" I'm like, "Well, it reads through in this case 'cause the next three to four things after it look and feel just the same way in terms of you're gonna look and you're gonna say, 'Okay, they Same brain region, haploinsufficiency. Like, if that worked, this should work.'" We think it's gonna unlock a significant amount of value beyond just the program, but actually into the platform. Like, when do you get platform value as a product company? It's when you can make a plausible claim that things can really read through, and I think this is that, and I think people will see that once we start talking about it more publicly. Great. Well, we look forward to hearing more about the next program potentially later this year. Just gonna scan the audience for any questions. Please. Can I just ask quickly, can you just talk about the value of mediating regulatory RNA versus mRNA? Yep. You want to repeat the question first? Yeah. The value of targeting regulatory RNA versus mRNA. Correct. Right. Couple things. I think traditionally, but I'll say there's caveats to this, targeting mRNA many times was used for downregulation, but there are of course examples of where you can do splice switching for upregulation. You know, what I would say we have found as an advantage, aside from just the upregulation writ large, is that it goes back to the basics of the biology, which is every gene relies on these RNAs to control their expression, and these RNAs, these regulatory RNAs, are persistent throughout life. We believe that opens the aperture for a lot more opportunity for upregulation than actually doing splice switching and targeting mRNA. The reason is that every gene makes a different amount of sort of non-productive mRNA, which is a target for splice switching, and we're just not sure how robust that is in terms of the amount of indications you can go after. Whereas in our own hands, we think that actually there's quite a lot of different indications you can go after in terms of upregulation. Well, thank you everyone for joining us and thank you for the time. Thank you so much. Appreciate it.