Chardan’s 9th Annual Genetic Medicines Conference

Oct 21, 2025

All right. All right. Why don't we get started? Good afternoon. I'm Guo Lifshitz, a biotech analyst at Chardan, and welcome to this session on gene therapy in the lung and cystic fibrosis and beyond. To frame the discussion, cystic fibrosis is an example of a rare disease where the scientific advances over the last 15 plus years have really transformed the outcomes and the quality of life for patients. It's also generated around $11 billion in sales in 2024, I believe, for Vertex, which is the major player in this space. There is a sizable fraction of patients, some 15% or so, whose mutations in the CFTR gene can't be addressed by current modulators or who can't tolerate modulator therapy. There's been a longstanding idea in biotech, of course, that if you can figure out a way to get a normal copy of the CFTR gene to the airway, you can treat those patients and perhaps more within the population. It's really only been within the last few years that this promise has started to be realized. In this session, we'll talk about the challenges and advances in gene delivery to the lung, the key clinical and regulatory considerations for cystic fibrosis for near-term success, and also the broader opportunity. I'm joined by our participants here. We have Dr. David Kirn, Co-founder and CEO of 4D Molecular Therapeutics, Dr. Sebastian Aguir, Co-founder and Head of Development at Carbon Biosciences, and Eric Pastor, CTO of SphereVant Sciences. Thank you guys for joining us today. Maybe to start off, I'd like to have each of you introduce yourselves and your company's pipeline. Let's start with Dave. First of all, thanks for having us here. I'm David Kirn, Co-founder and CEO of 4D Molecular Therapeutics. We're a next-generation AAV genetic medicines company using directed evolution to invent customized vectors for a variety of different tissue targets. Our lead products are in the retina and in the lung airways. Our lead product is 4D-150 for wet AMD and DME. We also have a geographic atrophy asset, 4D-175, which has an open IND. For airway diseases, our lead product is 4D-710 for cystic fibrosis, which uses a targeted and evolved vector to deliver the CFTR transgene. Great. Sebastian. I'm Sebastian, Co-founder, Scientific Co-founder of Carbon, Head of Platform Development. Carbon is a preclinical company that started a little over two years ago, developing a new set of gene delivery vehicles based on parvoviruses. These are structurally similar to AAV, leveraging a lot of the learnings after 30 years of experience with AAV, but also bringing some new biology. We identify natural capsids and use them for specific applications, such as CF, in particular for lung delivery. We have other pipelines also for systemic applications and a second set of vectors for cardiac applications. Great. Great. Hello, everyone. Eric Pastor, Chief Technology Officer, scientific advisor for SphereVant Sciences. We are an in vivo gene therapy company focused 100% on respiratory diseases. We lead, of course, with CF. We currently have an open IND, phase one to clinical trials using our AAV SP101, how it's termed. One thing about SphereVant is we are also 100% focused on maximizing delivery, maximizing gene expression in the CF space. To that end, our platform also utilizes a proprietary small molecule augmenter, and that is part of our clinical trial as well, SP101 followed by augmenter. Great. Maybe let's start with the challenges in the space that have historically limited the progress on gene delivery to the airway. Can you guys talk about what those have been with respect to things like transduction efficiency, safety, et cetera? We can start with Sebastian, calling on you. Yeah. I think that's been a combination of physical and technological barriers, probably an immaturity thinking in what do we know about the lung in particular. This is a very sophisticated tissue with more than 10 different cell types. What initially was identified probably as one of the low-hanging fruits for gene therapy, together with hemophilia, immediately demonstrated that it wasn't quite easy to get there and target the right cells. I think, again, a combination of lack of understanding together with limitations in the delivery systems and a complex tissue also to reach. I look back where some of the first AAV gene therapies targeting CF were going back 20, 25, almost 30 years. Using endogenous AAV, AAV2, you're using the full-length gene with no promoter. At that time, delivery and then expression of the payload was always just a big challenge. That's a challenge where you're seeing a lot of advances now that companies are overcoming. I mean, this is learnings after 20, 25 years of AAV in the lung. David, anything to add? Yeah, I think when we think about delivery to the lung, we think about, first of all, what's the best method to deliver. We felt that it was aerosol delivery. IV would certainly be fine as well, although the doses would be much higher. We know there's a lot of toxicities associated with high doses IV. We elected to do aerosol delivery. We use a routine clinical device known as the AeroEclipse 2, which had already solved the problem of delivery to the lung airway with this mist that's produced. Each droplet, based on its size, deposits somewhere different in the lung airway. From a starting point, we had the ability to target the entire airway very evenly just by using that device. The second issue was the mucus barrier. We wanted to use directed evolution to invent a vector that could get through the mucus barrier lying over those target cells. The third thing is that there are antibodies in the mucus. We wanted to evolve a vector that was highly resistant to pre-existing antibodies in the population. We targeted our directed evolution process using a billion vectors towards the best vector to do that, to be stable and non-aggregating in that AeroEclipse 2 delivery system, getting through the mucus barrier, resisting pre-existing antibodies. We invented A101. Clinically, the results we're seeing are just off the charts in terms of reproducible transgene expression throughout the airways, including all three major cell types of the goblet cells, the ciliated cells, and the basal cells, which are essentially the stem cells as well. In terms of the different cell types within the airway, I think there's been some data in recent years that for cystic fibrosis, ionocytes might be important in expressing the CFTR in particular and contributing to disease modulation. Are you guys able to deliver to that? To what extent in your experience in clinical or preclinical settings is that playing out? Yeah. I'll start by saying we have a great partnership with the Cystic Fibrosis Foundation. They have the best scientists and physicians in the world looking at this disease. They don't know where you need to express. You'll ask them. You'll say, yeah, ionocytes have a very, very high expression level, but they're a very, very rare cell type. It's unlikely that that's the only place that you need to express. We figured we weren't smart enough to pick the right cell type. We hedged our bets by saying, let's get a vector that targets goblet cells and ciliated and can get into an ionocyte and a basal cell. Let's use a ubiquitous promoter and express from as many different airway cells as possible. They certainly supported that approach. Right. That's interesting. There's some good 4D-710 data, I think, on the ionocytes, but we are not 4D-710, so it's fair to go broad. Yeah. We just saw in regards to the ferrite too, yes, the ionocytes are important, but that's not the only thing, right? We could transduce other cell types that could rescue that ferrite. It wasn't necessarily ionocyte dependent only. To Dave's point as well, all the other cells can play a role. We've seen mucosal cells play. If you can transduce those, if you can get CFTR expression across the broad range of those cell types, that's probably going to lead to a meaningful effect. We did extensive experiments also in collaboration with this foundation. They helped us actually to identify transduction in ionocytes. We specifically looked at it. We saw transduction and expression of actually high levels of CFTR in those cells. In our case, we also target secretory cells in general, club cells. The foundation was really key in helping us to get the reagents and the assets to do this characterization. I agree that ionocytes is not only the answer. You probably need to hit more cells. We look at it and we see it, which is nice. Have you done the single-cell RNA sequencing and seen that distribution at that level, gene expression, not just delivery, but actual expression of CFTR? Have you gone into... Not through mRNA. We kind of did different imaging mostly, but we see the protein and the markers with ionocytes. Again, the foundation is very good in having all those reagents. Yeah, that's really come to the forefront, a lot of the available imaging tools. Exactly. I think, yeah. No, that's encouraging. I mean, it's also good, I guess, with the inhaled delivery. In many cases, it allows you to have a ubiquitous promoter and target all of your targeting all the cell types, but you're also likely to express in all the cell types that you're delivering into. Any other advances in the technology or scientific understanding that you guys wanted to flag that have accelerated the progress here? Otherwise, we'll move on. I would just say the novel capsids, the approaches of those, even thinking ahead and maybe just jumping ahead, like if we're forward thinking, some of the advances, even more of the novel serotypes that are coming in to enhance the infection uptake and all of that. I see a lot of room for advancement there too. One of the aspects that we like about our capsid is it derives from a virus that is naturally found in patients with CF, so found naturally to cross the mucus barrier. It is a larger, it has a naturally larger payload, which allows us to use the full-length CFTR. We see that that plays a role in having a little higher potency when we compare to other platforms. Got it. Maybe let's turn to discuss cystic fibrosis in a little more detail. Can you explain for us the overall cystic fibrosis market and the patient segments with the unmet need that are currently not addressed by CFTR modulators? Maybe Eric, let's start with you. Sure. Our 100% focus is on that class 1 mutation, severe unmet need. These patients are rough, and not just the class 1s, but those that are non-responders to the modulators or that are non-eligible for those. That's the 10% to 15% of the population that we're focusing on immediately. Adult populations, expand that into adolescents, expand that into peds if possible. That's our number one focus. I think we're all in the mutation-agnostic gene delivery. There's no reason why this cannot expand further into the class 2 and above, those that are on modulators. We talk about combination therapies in the future, something to investigate further. Number one right now, we have to take care of those class 1 patients. Got it. Do you guys have any other thoughts on that? Yeah, no, I think that's how we're developing this. We'll get approval in the patients who either are not amenable to modulators or who can't tolerate them. There's actually a tolerability issue in some patients, and then move quickly into the broader population in combination with modulators for patients who are getting suboptimal responses. Got it. To level set here, what are the key efficacy metrics that are typically used to support cystic fibrosis approval? What kind of result is considered clinically meaningful for those? Yeah, so this is an interesting area because FEV1 is what Vertex used. Everyone says, oh, it's got to be FEV1. That's the validated endpoint. If you look at FEV1, it's effort dependent. It's extremely variable within the same patient, let alone between patients. The only reason Vertex could do that is that they were willing to do 400 patient studies, and they can actually get a signal. I don't think any of us is in the business, especially with this smaller subset of patients, rare disease. None of us want to do 400 patient studies. We've been thinking a lot about what are the endpoints that in totality together could lead to an approval with, say, a small randomized or even a single arm study of 40, 50 patients, which is more typical of rare diseases. We've been looking at, in addition to spirometry and FEV1, lung clearance index, which has been used for approvals in pediatrics. It's a much more sensitive endpoint, much more reproducible. It's got a better dynamic range early on in the disease. We like that, and we're seeing some pretty interesting results there. There's a well-defined kind of threshold for clinical meaningfulness and also what you could see with modulators like Orkambi. That's well-defined, so we like that. High-resolution CT scanning is another one that's interesting to look at mucus plugging. Obviously, for cystic fibrosis, some very, very sophisticated, high quality, and validated quality of life instruments. You can really look at that, plus the biopsy data showing expression, showing that it's durable. I think if you look at the totality of that data, we're going to have a pretty strong signal to argue for approval. I think just relying purely 100% on FEV1 in a relatively small single arm study is going to be problematic. You've got to look at a number of different endpoints. Do you think regulators recognize the challenge? It is up to us to educate them. I think they are aware of it. Certainly, their pediatric approvals with CFTR modulators have been driven by this lung clearance index endpoint. They recognize that FEV1 is effort dependent, so you can't necessarily do it in pediatrics. I think it's incumbent upon all of us to educate analysts, investors, regulators, patients, and physicians to say we need a more robust panel of orthogonal endpoints to get approvals. Not all the metrics are interesting, for example, related to the quality of life or improving the quality of life, like reductions in the use of antibiotics or less cough, things that you can quantify and give you an idea also how things are performing. Right, right. Yeah, very similar. Everything that he said as well, reduced exacerbations as well. We put a little bit more emphasis, just based on the variability my colleagues here have mentioned, a little bit more emphasis on the biomarkers, especially with the low number of Ns. We want to see that, OK, here's the vector genomes got in. Are we seeing mRNA? Are we seeing protein? Are our assays robust and specific enough that we can make very good determinations if the error bars on FEV1 are so large? Can we see something a little bit more precise and specific, like mRNA? For us, that's a big one that we try and promote. Eric, I wanted to come back to something you mentioned. You talked about the augmenting component there. Can you expand on the impact that that has for your therapy? Sure. Yeah, that's a major component that we found. Again, going back to how do we maximize not only the delivery, but expression. Our three components of our molecule, we have a novel capsid that was evolved on human airway epithelial cells in vitro. We felt good about the specificity, the ability to infect or bind, infect, internalize into human airway epithelials. A major component now is the translocation to the nucleus to get your gene expression. That's where we found the proprietary small molecule augmenter can really give a boost in expression. We're talking 100x in vitro. We also see this in vivo in our non-clinicals under CF ferrets. We did, with some of our academic collaborators, a really nice mucociliary clearance study in CF ferrets and found that it's critical that our molecule, we need that augmenter to get to therapeutic levels of mRNA and above. It's a booster. It's an augmenter. We feel that's something that's going to put us over the edge. If our capsid and our mini-gene and expression of mini-gene can almost get us there, it's going to be that augmenter that's going to bring things up to therapeutic levels. Sebastian, you mentioned that you guys are delivering the full-length CFTR. What is the impact that delivering the full-length versus the delta R? What is now, the delta R in particular, again, has been developed to really be able to package it in AAV capsids. You have a little reduction in the potency when you compare side by side. We think of that as a boost. The idea is that providing a natural copy of the protein and removing any possible risk of new epitopes being formed and things that can occur eventually with these mini-genes type of candidates. We also have made some tests with augmentators as well. We see the benefits. At the same time, via optimization of the vectors in the production or other aspects, we see that also kind of matches without the use of augmentators, probably related to the narrow tropism that we see for these capsids and the idea that we also provide the full-length CFTR. David, you guys, as you mentioned earlier, have shown widespread transduction. You've also had a regulatory update to an extent where you talked about adding cohorts, exploring lower doses, and the update regarding your phase two plans. Can you walk us through the key results to date and give us a sense of what we should expect from your data update later this year? Sure. We've treated on the order of 16 patients to date with aerosol-delivered 4D-710. What we've seen, first and foremost, is great safety, particularly at the three lower dose levels. Our phase two dose actually is going to be the lowest dose level. We actually had to dose decrease because we were getting such a high level of expression. In terms of the expression, we look by RNA and by CFTR protein expression. What we see is on the order of anywhere from 50% to 95% of the cells staining for RNA by in situ hybridization and then 90% to 95% of cells overexpressing CFTR protein. We see it in the ciliated cells, goblet cells, basal cells. At the highest dose level, we started to see it in the interstitial cells, which we thought was a bad idea. We actually dropped the dose, so we got more of a physiologic pattern. We're thrilled with the expression levels we're seeing. It's a very clear dose relationship. We've been looking at FEV1, lung clearance index, high-resolution CT scanning, and quality of life. We'll give an update later this year on all those endpoints with a particular focus of the nine patients at these two lower dose levels where we were seeing kind of more physiologic patterns of expression, not this massive overexpression. That's nine patients with anywhere from 3 to 15 months of follow-up. We also are now getting late biopsies. Our initial biopsies and brushings were at four to eight weeks after dosing. We're now looking at one to three years out and asking the question, how much of a decrease, if any, has there been from the early biopsy in the same patient? Asking the question because I think another big question for this field is what is the lung turnover rate, right? In retina, it's easy. It's lifelong. This is something that is fascinating. You go to the world experts of the CF Foundation and they cannot tell you. It's remarkable. It seems like in every other disease area we know. In mice, it is a year and a half turnover, which is longer than what people, I think everyone assumes it's like the gut for some reason. I don't know why people believe that. We haven't released the data yet, but let's suffice to say that you could expect multi-year expression. The lung turnover is not that fast, even in CF. We're worried that maybe in CF it'll be faster turnover. Yeah, disrupted. We will update that data. I think that's going to be a major important finding for the field. Exactly. It will illuminate, I think, how we think about these therapies. When do you re-dose? I think in the lung, we are going to ultimately want to re-dose. I think others have shown you can. We expect to be able to do it. The question is when and how do you decide when? Yeah, that was going to be my next question. OK, I'm not going to get too far ahead. Sorry. Yeah, I mean, again, in principle, it sounds like it can be re-dosed. How do you think about what that looks like? You've added a re-dosing cohort to the study. The question is broad for all of you. What does that re-dosing paradigm look like, and how do you decide when the optimal time to do so is? Yeah, we just announced another investment from the CF Foundation in our company of another $11 million. That puts them at $32 million to date, which we're incredibly thankful for, plus their scientific and medical capabilities. What this is really focused on is the phase two expansion. We think we found our correct dose. We'll get an additional six patients at that dose level. We'll also start to explore re-dosing in some number of patients. We're still sorting out exactly how to decide when to do that. We can get into some thoughts about that. Then phase three readiness, going back to FDA. We've had initial discussions, going back with proposed primary and secondary endpoints for the pivotal study, deciding what the control group is going to be. Is it going to be pulled out of this reach study that the CF Foundation is running, where it's kind of an external control group for all of us? Will we have a small internal control? Those are the kind of things we'll want to sort out. Right. Eric? Yeah, we're thinking very similarly. Durability is going to bear out in the clinical trials. What does that patient tell us? Still have a lot of work to do to understand the cadence. We're definitely thinking multi-year as well, just based on our predictive, whether it's animals, what we know about cellular turnovers. We're going into this eyes wide open that this viral vector is going to exist episomally. It's going to eventually dilute out. Re-dosing, we've wrapped it into our commercial assessments. It's not as daunting as we had originally thought once we mapped it out. If we have to re-dose, if it is going to be multi-year, how does that fit in with the available therapies out there? What is the immune system going to look like? Immunosuppression strategy. We've talked about it. We've mapped it out. Ultimately, the patients are going to have to tell us that durability and re-dosing details. Sebastian? Yeah. Thinking in the different components that you have here. On one side, what's the turnover? Where the cells are going to start shutting down? Then on the other side, immune responses. How prevalent are the immune responses? I believe that in the lung, maybe more permissive than re-dosing in vivo, I mean systemically re-dosing, which can be more beneficial. Something that the capsid that we use is very different to AAV, so no cross-reactivity. You guys can re-dose with our capsid maybe, but not have antibodies or vice versa. Good point. Yeah, for sure, we will learn a lot about key aspects, I think, that can open really new doors for the treatment of cystic fibrosis and beyond. I guess just sticking to that kind of commercial potential point, we talked earlier about how the greatest unmet need is within that 10% to 15% of patients who are ineligible and then plus the ones that are intolerant of current modulators. If the benefit-risk looks favorable, how do you think about the opportunity in that broader segment of the population, either as a single agent or as a combination therapy? I think, look, every complex, difficult disease ends up getting treated by a combination therapy, two, three, four different agents, right? I mean, that's how we cure most diseases or at least make a huge impact. That's going to happen here. I think the modulators may, in fact, make our transgene products work better. It may be purely additive or maybe better. I mean, you can imagine a patient who's partially improved with modulators may have even less of a mucus barrier. You may even be able to drop the dose further, have even lower cost of goods in that population. I think there's a lot of reasons to think it could be additive or even synergistic. I think that's where we're going to, we're eventually going to get to. I think that's going to make a lot of sense, to get a gene therapy on board in these patients and fundamentally modify their disease at its foundation and then use modulators as needed to bolster that. Eric? Yeah, I would agree. It's going to be interesting discussing with regulators kind of maybe some non-clinical packages that they would expect to see once you're talking about combinations, the different types of modulators. Where does now your cystic fibrosis express gene and express protein? How does that work in accordance with the modulators? It'll be interesting to see the regulatory feedback. Commercially, there's no reason why we can't expand. Class 1 patients, again, we have to show the success. We're going to learn a lot from them. We understand especially how the modulators can impact adults, right? OK, that gives us a good pathway now for the adult population of the other classes. What about then from a manufacturing, CMC, and COGS standpoint? That's an area I will let you start there. Exactly. I've heard a lot from my colleagues too from a manufacturing standpoint, the invest early, which resonates a lot. As soon as you start getting in, you draft your TPP. You're going in with your phase one, two, for example, on a very specific class. You're mapping out what that commercial looks like from a manufacturing standpoint, not just in the class 1s, but you're assuming that you're going to have to hit all of those populations. Factor in re-dosing. OK, this isn't a one and done. This isn't, I'm just going to treat every new patient and then I don't have to worry about them. Once you start compounding the re-dosing strategy on a manufacturing burden, if you just simply map out and say, I can make a few thousand doses per year per batch. Are you taking into account that first five years and maybe five years and beyond where you're not only treating new patients with the current prevalence there, but now you're re-dosing those patients that just got dosed the first time? Capacity, scalability, all those things that factor in, but COGS. I'm very circular with this. If you have the better product, the better molecule, the lower the dose. If you lower the dose, you're going to have more drug products at the end of the day. That's going to lower your overall cost of goods. The better biology you have, you can make more products, cost of goods, and then you can pass that along to the payers, to the patients, and all that. Start early. As soon as you get a TPP and you have designs of later stages, that's when you're mapping out your commercial manufacturing demands. David? Yeah, I think, look, I'm going to take a step all the way back and say that with gene therapy, sort of this kind of concept of one and done in these rare populations, while it can be transformative for patients, it's not a very good business model, right? Think about it. Like several thousand patients out there, we treat everybody once, we're done. There's no further market. That's not like most rare disease markets are good because you can continually re-dose. We ask the question, as a gene therapy, can we get to a point where we can treat either high incident diseases like wet AMD and DME, where it may be lifelong expression, but it's a high new incidence every year, or go into diseases like CF where we think we can re-dose, right? You have a sustainable market, and it's also good for patients. That's kind of how we got where we are. We felt we could use directed evolution to invent better vectors, which means lower doses, better delivery, lower cost of goods in a real viable market, in contrast to where people have ended up in hemophilia or other places or LCA2. I think here, having a better vector means lower doses. Also, part of our directed evolution is selecting for vectors that package very efficiently because that's part of the directed evolution, you have to package each time so you get something that manufactures very well. We've gone from initial estimates and by bringing the dose down in the clinic, obviously. We've gone from initial estimates of $100,000 per dose down to maybe, I'm not going to put a number out there, but potentially an order of magnitude lower. The other thing that's critical for this disease, I think, where we don't have the need in retina necessarily, is to go to suspension culture, right? It's ultimately much more scalable. Pharmaceutical partners or acquirers are much more comfortable with that. It's more sustainable equipment and everything else. I think moving to suspension, that's something we've also been working on and will be part of this phase two effort that's funded by the CF Foundation, is also that tech transfer of a suspension process to a commercial manufacturer. The more of these things you can do in advance, the more de-risked the program is, the more efficient your development. Yeah. That's what's critical really. Early on, we did a heavy investment in building our own process. We have a special case because of the different caps. It comes from a bocavirus. Nobody really out there could make it other than the scientific inventor. We had to quickly, in a couple of years, catch up with 30 years of AAV experience in manufacturing, something that we did. It was really transformational for us and for the product because it really improved not only the yields, but also the quality and translated to potency also. For us, it worked out. The heavy investment that we did early on worked out pretty well. We also were able to take it to CDMOs and put it in the hands of other people that can now make it and make it better than us. That's also great to validate, especially a new technology, and put it in the hands of other people, thinking that in the future, probably we may want to produce this in different parts of the world if things go well. I think that that's important, especially with a new technology. It worked out pretty well, our investment in CMC. Critical, yes. Great. The sooner, the better. Great. This discussion has focused primarily on gene therapy. There are a number of other viral approaches, as well as non-viral approaches that are being advanced for cystic fibrosis, including RNA delivery, gene editing, other viruses, et cetera. Several of those have also received support from the Cystic Fibrosis Foundation. How do you guys think about the competitive landscape as it's evolving in the cystic fibrosis space? What gives you confidence in the vector gene therapy approach? Maybe I'll start. Go ahead. I think non-viral approaches are very attractive in terms of payload capacity and re-dosing. On the other hand, they have been associated in the lung with some side effects, some toxicities. I haven't seen data to say that they can get reproducible high-level expression to anywhere close to what we're seeing with AAV. Biologically, these viral vectors, such as AAV, have evolved for millions of years to go from the surface of a cell straight to the nucleus and unpackage and drop their episomal DNA there. Trying to replicate that with a human-created synthetic product is going to be tough. I think the jury is still out there as to whether that's going to work. I think the viral vectors, as long as they're safe, are going to have a huge advantage in terms of the efficiency. The RNA expression, again, they're going to need delivery vehicles. Same problem there. You're talking about dosing every day or every week, versus dosing every one to two or three years. It's got a huge competitive advantage there. I think, again, I hope the RNA molecules succeed, but you're talking about very frequent dosing and the need for better delivery vehicles there, I think. Sebastian? I celebrate and I think it's great for the patients that there are multiple shots on goal. There is a support to really explore several approaches to deal with the problem. I agree with AAV also on some of the challenges, persistent challenges, especially thinking in non-viral. Those are going to be tough, in my opinion, as well. I think it's good to have different options. We'll see which one performs the best. I think you need a virus or something more complex in a way to really get to the right type of cells, and as David was saying, to the nucleus, which has been a challenge for 30 years. Yeah, not much to add. Although, similar to David's point, the long-term effectiveness of gene transfer and then existing there, I think that's the benefit right now for viral vectors. Got it. Great. In the last couple of minutes, I wanted to get your sense of the sentiment around gene therapy, particularly in the cystic fibrosis space and more generally in pulmonary delivery and more broadly as well from your conversations with investors, pharma, et cetera. As we've talked about in some of the other panels, there's been positives this year. There's been challenges this year, both on the clinical side, the regulatory side, et cetera. What's your take on the sentiment these days? How do you expect that to evolve going forward? This is one of the, we think of new technologies kind of going through this traditional phase of getting hyped up, then crashing down because this never is as simple as you think it's going to be in humans, and then slowly coming out. Ultimately, the people who succeed are the people who stick with it through the tough times and come out the other end. Gene therapy, unfortunately, we've gone through that cycle about three or four times. It seems like it's not been once. I hope it seems like with the Unicure success, that there's an openness to gene therapy again. I think the key thing that we all need to reiterate is high doses IV that have led to so many problems, the deaths, the tragic deaths we hear about in the news and other, is a very different situation than regional or local application to the retina or to the airway, right? You have to think about these things differently. We can't all get grouped together and thrown in the same bucket. I think we have to educate. I think the investors and others are getting there that the tragedies you see with high doses IV are not being seen with the local regional applications that we're going after. We have lower cost of goods, much better safety, much easier routes of administration that are routine clinically. This is going to be something that leads to a great commercial opportunity and not have all the baggage of what we've seen, say, in hemophilia, where you've got the toxicity, you've got the high cost of goods, you've got to charge $1 million or $2 million to be successful. I think hopefully we're seeing that separation and also a separation versus traditional vectors versus next generation vectors, which we're all here working on. Got it. You guys? Yeah, I agree on the kind of the signs that things are looking better probably for next year. It will be interesting to see. I also agree on this idea of exploring together with your technology, your vector, your delivery system, exploring smart ways to deliver. How can we avoid systemic exposure if we don't need it? There are successful examples at uniQure, as Bio also using intracardiac delivery. The kidney has been historically very elusive, and there may be ways to avoid systemic exposure to get there. There are others that are still tough, like skeletal muscle that you need to reach and probably need to go systemic. I think case by case, you need to think in ways not only in your delivery system, but also what else can you leverage that is already out there in the clinic to maximize the effect and reduce toxicities and any adverse events. Eric. I'm excited about all these technology innovations that are current and that companies are investing in. Strong science, strong platform, strong technology, that's going to make products look better. We're talking about AI-derived capsids. I see a lot of companies investing in that next generation manufacturing. These are leaps and bounds that are going to make product and drug development faster. It's going to accelerate development and come up with better drugs to treat diseases. Fantastic. On that note, that brings us to the end of the session. I'd like to thank all of you again for the great discussion. Thank you all for listening. Thank you. Thank you.