Welcome to this session focusing on new applications of genome editing technologies. I'm Geulah Livshits, a biotech analyst at Chardan. And over the past 10-plus years, gene editing technologies, and most notably CRISPR-Cas9 nucleases, drew a lot of attention for their ability to be readily programmed to cut specific stretches of DNA to disrupt genes or regulatory regions in the genome as a way to durably silence or upregulate a gene, as we've seen for NEXZ or Casgevy. And this was accelerated by the pretty straightforward programmability of the guide RNA component. But in the last several years, we've also seen major leaps in protein engineering and analysis. And those have enabled scientists to advance other non-CRISPR nucleases and optimize other DNA-modifying enzymes to expand the applications of editing technologies. So in this session, we'll discuss how applications of some of these technologies for gene insertion or making larger changes in the genome and for targeting viral genomes can be deployed. And I'm joined by our participants here. We have Erik Aznauryan, Co-founder and CEO of HarborSite, Gabriel Cohn, CMO of iECURE, Cassie Gorsuch, CSO of Precision BioSciences, and Albert Seymour, CEO of Seamless Therapeutics. Thank you all for joining us today. And let's start the session by having each of our participants briefly introduce themselves and their companies' tech and programs. And let's start here on this end. Sure. Yeah, good morning, everyone. I'm Cassie Gorsuch. I'm the CSO at Precision BioSciences. Precision is obviously a gene editing company. We are not using CRISPR-Cas like many others in the field. We have a proprietary gene editing technology that we call ARCUS. It's wholly owned, developed at Precision. It's a nuclease-based system that we can engineer a single protein to recognize DNA and cut DNA. And so we think it has some unique features that really make it attractive for therapeutic gene editing. And we're trying to leverage that technology in ways that we think really highlight some of the advantages of our platform as it compares to other gene editing technologies. One of the exciting things today is we are actually using our technology in partnership with my colleague to the right here with iECURE for clinical gene insertion. And I'll hand it over to Gabe to introduce. Thanks, Cassie. Good morning, everybody. I'm Gabe Cohn. I'm the Chief Medical Officer at iECURE. iECURE was founded a number of years ago basically from the work that came out of Jim Wilson's lab. The focus, initial focus, is on OTC, or ornithine transcarbamylase deficiency, which, again, he's worked on for over 30 years. As Cassie indicated, the approach that we take is a gene insertion approach using the technology that was developed with Precision. It's a very targeted, specific gene insertion into safe harbor PCSK9, and we actually plan to use that as a platform, if we're successful with OTC deficiency, expand that into other inborn errors of metabolism. Great. Hi, everybody. Albert Seymour, CEO of Seamless Therapeutics. Seamless was founded based on technology coming out of Frank Buchholz's lab in TU Dresden. And what he was able to do was to take the properties of Cre recombinase, which has been used since the 1980s, and using directed evolution can program that to have the same activities that you enjoy with CRE at locations in the genome that we want it to go to. And so utilizing this programming, we can take these enzymes, integrate DNA, or delete DNA, or invert DNA at specific regions in the genome. And we're developing that as a technology of really focusing on gene integration or gene insertion, where we can do it where we can either go into safe harbor sites. Or I think one of the big challenges that the field is facing is how do you regulate gene expression? Can you actually integrate a cDNA under the control of an endogenous promoter? That's another area that we're focusing on at Seamless Therapeutics. Hi, everyone. I'm Eric Aznaurian. I'm co-founder and CEO of HarborSite and also a Blavatnik Fellow at Harvard Business School. At HarborSite, we are also leveraging the power of recombinases to make large insertions into genomic safe harbors in the human genome for applications in inborn errors of metabolism, in vivo CAR-T, and beyond. This work has stemmed from George Church's lab at Harvard Medical School and has been funded by Novo Nordisk prior to our spin-out earlier this year, and the big value of the large gene insertion, of course, is that you can address multiple mutations affecting a specific gene and leading to the same phenotypic output, and so we are focusing on making those large insertions into safe harbors that we previously discovered to address very large patient populations suffering from specific genetic diseases. Great. So some of you guys started alluding to this in your overviews. But talking about gene insertion, can you expand on what limitations these types of approaches address and how they differ from, let's say, traditional gene replacement therapy as well as gene correction techniques like prime editing? Yeah, go ahead. I'll start off, so I think with gene integration, one of the aspects that really addresses some of the current limitations is the ability to insert large DNA fragments, and as Eric had just mentioned, there are a lot of diseases that have multiple mutations that span the entire gene, and so going after one mutation can work in certain areas, but not across all of them, and that's a key advantage of these recombinases or gene integration, where you can put these large pieces of DNA into it. I think the second aspect is being able to position it in the genome where you want. You can use a safe harbor if you want to secrete something or express something at high levels. You can then take that whole cDNA as a functional wild type in loss of function disorders. By targeting it into a gene of interest, you also have the ability to perhaps do a knock-out or knock-in. So you can take that cDNA and put it directly into the gene that's mutated and engineer it such that only the wild type form is expressed. And this is important in diseases that may have, say, a loss of function, but a little bit of a gain of function with respect to forming enzymes. And so some of these diseases where you have multiple amino acid changes within the protein have loss of activity, but it forms a tetramer or a dimer. And so by knocking out those mutant alleles and expressing the wild type, you can overcome some of those challenges. Yeah, you know, Albert addressed this perfectly already, but I would also highlight some of the applications where multiple genes have to be inserted into the genome, and that cannot be addressed by small genome editing systems, and we see this more often in vivo CAR-T space and generally in CAR-T space, where the next generation, fifth and beyond generations of CARs are requiring multiple insertions, and that would be able to address that with a gene insertion system like ours, and then beyond that, even with the rare genetic diseases, I think there are certain indications where you can go by inserting multiple genes addressing different mutations and generally similar inborn errors, so for instance, there are diseases like methylmalonic acidemia, propionic acidemia, where, of course, the manifestation is slightly different. but perhaps you can insert both genes irrespective of the specific mutation, the specific disease that the patient has to address both diseases with the same drug. That's something that, again, cannot be achieved by standard genome editing technologies. One area actually I'd like to focus on, aside from what my colleagues just suggested, is also the differentiation between traditional gene therapy or gene addition versus gene insertion. If you think about the most severe genetic disorders, they really manifest themselves very, very early on in life. There you're really talking about actively growing organs, high mitotic index. If you use a conventional gene addition approach, that donor gene or the gene of interest remains episomal. With each round of mitosis, that episomal gene isn't replicated, so it gets diluted out. Whereas if you do a gene insertion or gene editing approach and introduce, again, that gene of interest into the genome itself, or if you correct the genome, then that should be replicated in subsequent rounds of division, which means that that should continue to be effective in a growing organ in a young child, again, with these most severe devastating conditions. Got it. And so the type of indications that these are suitable for are, again, it sounds like young pediatric indications, things where you may need, let's say, a consistent amount of protein. Got it. So maybe let's dive into gene insertion a little bit more from a technological standpoint. It involves multiple components and variables that could be tested and optimized for a particular therapeutic goal or indication. So you have the choice of delivery modalities, the nuclease recombinase insertion site that you're putting it into, and then the construct design. So maybe I'd like to understand how each of those can be optimized and used to shape the product profile. And maybe let's start with Eric and then go to Albert. Yeah, of course, this is a matrix of different components that you all need to kind of put together to be able to address specific diseases. And all of this is very indication-specific. If you take certain diseases that are associated with secreted proteins, maybe then going into a safe harbor with a significant amount of expression in just a small number of cells would be sufficient versus if you go after things like cancer, where you need to edit all cells, that would be different. So we are approaching this through the safe harbor approach, where we have a promoter that is specific for a specific cell type inserted into a safe harbor and have a robust, durable expression of the therapeutic gene that is producing a protein that's secreted. And that's kind of how we address that. Maybe just to expand a little bit on that, I think in each of those components, so delivery, construct design, so we're talking about integrating a piece of DNA into the genome. So one of the key things we have to do is be able to deliver and get DNA into the cell so that you can get that DNA into the nucleus. The other aspect is the ability to repeat dose. So can you decouple those? Can you get the donor construct into the cell, get to the nucleus, but then be able to come in perhaps with an LNP or a non-viral approach with your recombinase or your whatever mRNA that's producing a protein so that you can then continue to dose? So for example, if you took AAV and you have the donor construct, you can utilize the properties of AAV that are very efficient in getting that DNA into the cell. I think to Gabe's point, you don't want to use that. It's been traditionally used with what's called traditional gene therapy, where you would then have a promoter express that. But imagine if you took that construct and you did not put a promoter on it. You really just put the cDNA of what you wanted to express with some unique sequences on either side that might be recognized by your recombinase, in our case. You can use that. It sits in the cell as an episome. It's not expressed. So it can help with some of that safety. You don't need high doses because you just have a few of those within each cell that you're trying to target. And now you come in, depending on the cell type that you're interested in, and repeat dose with your LNP or your non-viral approach with the mRNA. The DNA from the AAV sits in there, and then you can pulse, if you will, the enzyme that's responsible for doing that DNA integration. That gives a lot of flexibility as you think about what diseases, what kind of tissue do you want to go into. I think there's a lot of discussion in the earlier panel around liver. Liver is more straightforward. But it also gives you the opportunity to start thinking beyond the liver as well, depending on what kind of indication, what kind of disease that you would want to pursue. Yeah, so iECURE is using ARCUS technology, as you guys mentioned. Can you talk about what's special about this approach? And let's start with Cassie, and then we'll go to Gabe. Yeah, I think one of the things that really stuck with me from the last panel is you need to select the right tool for the right job. And I am a firm believer in that. I think that there's a place where different types of technologies can really shine. And so it's about matching the advantages of your technology with the indication and the edit type that you're trying to achieve. One of the great things about ARCUS nucleases is they create a unique staggered overhang cut. And that overhang cut allows for very high efficiency gene insertion in dividing cells and non-dividing cells. And that is a little bit blasphemy if you read the literature on gene insertion via homology-dependent pathway in non-dividing cells. It's absolutely possible if you have the right tool. It's about using the right tool for the right application. And so we think the ARCUS editing platform has some unique advantages to allow for high efficiency gene insertion in the case of iECURE in dividing cells in small babies, but also in adult populations because of that staggered overhang cut allows for homology-mediated gene insertion. And it allows you to do some more sophisticated things. We just actually published a paper demonstrating the ability to insert DNA and remove DNA in one step. And I think that was a point made earlier is that some therapeutic indications are going to require you to overcome a dominant negative effect where the mutation has deleterious effects itself. And so you need to supply a wild type copy and remove a mutant copy. We can do that in a single step because of our homology-mediated gene insertion. So anyway, I think that the iECURE approach using the ARCUS technology is a really great example of applying the right technology and the right indications. Gabe? Sure. So in terms of, we have a phase one, two, three clinical program right now. It's actually, we've been cleared to do that in four regions in the United States, the United Kingdom, in Spain, as well as in Australia, and we've recently presented our 10-month data, and this is a patient who was six and a half months of age at the time that they were dosed. Now, one thing is our indication is ornithine transcarbamylase deficiency, and the patients we're studying have neonatal onset ornithine transcarbamylase deficiency, and why is that significant? Because this is a very rapidly progressing disease. It occurs very, very early on in life, first week of life, usually the first two to three days of life, and again, very devastating. The standard of care, medical standard of care, which requires scavenger medicine as well as protein restriction, unfortunately is not adequate. These patients continue to have high ammonium levels, which is neurotoxic and hepatotoxic, so they have these hyperammonemic events, hyperammonemic crisis, and longer term, which is just a couple of years, they either wind up succumbing to the disease or they require liver transplantation, so we basically treated a patient with this neonatal form of ornithine transcarbamylase deficiency at six and a half months of age. This is a patient who was on standard of care medication, had experienced these hyperammonemic events. Following therapy, within three months, we were able to discontinue the scavenger medications because of the biochemical efficacy that we were able to demonstrate. The patient has remained off of standard of care medicine from month three to month 10 post-treatment. Patients experienced no hyperammonemic events, no hyperammonemic crisis. If we look at the ammonia levels that occurred after removing a standard of care compared to pre-treatment, we've been able to reduce that by about 50%. Most importantly, the patient was on the liver transplantation list, is off the liver transplantation list, does not require any kind of protein restriction, and is basically living about as normal a life as any one and a half year old or two year old can live. And I would just add at the molecular level, just to highlight something Gabe said earlier, if you think about a traditional gene therapy, certainly during the course of that child growing over the time that Gabe just mentioned, that AAV vector, if it's not inserted into the genome, is diluting out. And so that therapeutic effect is going to wane over time. And so we know based on the fact that this baby is living this normal life that we have achieved gene insertion and that that therapeutic effect is coming from an inserted copy of the healthy gene. Got it. And in terms of the insertion that's inserted into the PCSK9 locus? That's correct. Got it. Yeah, so PCSK9 is serving as our safe harbor. What was the rationale for picking that? First of all, there's a small percentage of the population that have PCSK9 mutations that aren't able to produce any PCSK9. They actually live a long life unencumbered by any cardiovascular disease. We know that individuals, again, that have cardiovascular disease are treated with inhibitors of PCSK9. It made perfect sense to be able to target that particular region. Got it. So there's a side benefit potentially. Yeah. Makes sense. And what made OTC deficiency a good starting indication for proof of concept for this overall approach? Yeah, that's a great question. So first of all, as I mentioned, this is a very, very devastating disease that progresses rapidly. As a result, as we look at the disease course and look at the potential risk-benefit profile of our therapy based on our non-clinical data and compare that to the risk-benefit of standard of care, we were able to justify introducing this into babies. Now, rewind just two to three years ago when we met with the agencies. To talk about a gene editing approach in a baby was unprecedented at that time. So we really had to pick a disease that really we were able to justify the risk-benefit considerations. The agencies initially came back to us and said, "Well, why don't you treat adults?" And the answer to that was, "Well, first of all, these babies never lived to adulthood. Second of all, even if you treated adults, we wouldn't, again, where our liver really isn't that actively dividing, we wouldn't necessarily be able to demonstrate that the mechanism is effective to be able to translate into children," so it really made a lot of sense for us to get into this. The final point I want to add is because this is a devastating disease, we could look at clinically meaningful outcomes in a very short period of time in a small number of patients to be able to demonstrate this proof of concept. Great. So maybe coming back to the technology itself, what's the state of the art regarding off-target editing and unintended on-target site modification and analysis thereof in terms of these types of technologies? Yeah, I mean, I can speak to that. So we have a phase one trial we're running right now on the opposite end of the spectrum from very rare, in hepatitis B. And so if you think about sort of what that indicates is, I think regulatory agencies have a clear line of sight to first-in-human studies using gene editing technologies, even in large indications, global indications like hepatitis B. And so we're running a global trial with five different sites all across the globe. So we've had a lot of regulatory experience specifically on off-target editing. I think if you think about what we just talked about in the last panel, there have been many who have come before, and there are many that are coming now. And so I think the path has pretty well been set on expectations around off-target editing and what that package needs to look like. It is an extensive package, obviously. It's an important safety consideration. You need to characterize where, if you have any off-targets, where they are. I think the expectation isn't necessarily that there are zero off-target edits. It's understanding the potential impact of those off-target edits and balancing that against the risk of the indication you're going in. Hepatitis B has no cure today. People live with chronic infection their entire life, and they succumb to liver cancer. And so it has to warrant the approach and understanding where your nuclease has effects and what those effects are is definitely part of the process. But I think there's a pretty well-established regulatory path now. Al or Eric, you guys are using recombinases. So how does that fit into the kind of potential off-target profile and other unintended consequences that we should be thinking about? Yeah, so at least as we go through and do the programming and the identification of where we want to put and engineer the recombinase to, one of the things that's unique about recombinase, and I'll speak specifically around the Cre or the tyrosine recombinases, it has a 34 base pair recognition site. And so you can actually take that and look across the genome and say, "Are there any other areas in the genome that harbor that particular site?" So that gives you the flexibility to start building in some of that on-target specificity preclinically. And so that's where we're focusing a lot on that. You can also utilize, because we're doing gene integration, even preclinically, because you're putting something into the genome, you can use that almost as bait, and that's how we do it. So we can go and look, "Is that gene integrated anywhere else in the genome?" You can look where maybe there's some overlap of that 34 base pair, maybe it's 50% identical or anything like that. You can specifically go to their sites, but some of the sequencing, the whole genome sequencing capabilities also allow you to just scan the genome and look, "Do you see that gene somewhere else in the genome?" Because it's unique. It'll be the cDNA. It's not the whole code. Right. Right. Eric. Yeah, and in addition to the larger site compared to standard guide RNAs, there's also another feature of recombinases, specifically tyrosine recombinases, in their mechanism of action where they don't actually make double-stranded breaks in the DNA, which are often associated with indels and translocations and things like that. Just by using this class of enzymes, we avoid those kind of scars off-target or on-target in the genome. Got it. So you just have to look for where it inserts. And based on the engineering or optimization, you kind of have a sense of the type of targets that it inserts onto, and you can scan for those ahead of time. Yeah. Got it. So maybe let's talk a little bit more about Hepatitis B. You started talking about the program and the approach there, but can you explain a little bit more on the strategy and the data to date and what made it an attractive indication for you to pursue with the technology? Yeah, of course. So one of the other features of ARCUS nucleases that I think make it well-suited for hepatitis B gene editing is that it's a very compact nuclease. So it's a very small protein. It's encoded by a very short mRNA sequence. We use lipid nanoparticles for delivery in our hepatitis B program for delivery to the liver. But I think having that short sequence mRNA allows for high-yield, high-quality mRNA that gets packaged into your lipid nanoparticle. And in an indication with liver infection, a viral infection in the liver, we really prioritize safety of the LNP and safety of the mRNA inside that LNP. And so having a small nuclease allows for, we think, an overall improved safety profile for delivery. Also, that small nuclease, the target here is to eliminate cccDNA. cccDNA is the viral genome that persists forever in people who have chronic Hepatitis B, and the goal in the field for forever has been to get rid of cccDNA. It's well accepted if you eliminate cccDNA, you'll cure the infection. We've never had a tool that could actually do that, and people have tried CRISPR-based approaches and have really struggled to get good targeting of cccDNA specifically. We have not had that challenge, and we postulate that it could be because the nuclease itself is much smaller than a Cas enzyme and that cccDNA is pretty compactly wound within the nucleus, and so it seems as though ARCUS nucleases may have a better accessibility to actually access the target site, cut the target site, and yield degradation of the cccDNA. And so that's really part of why we went into this indication was we felt like the technology matched well with the therapeutic editing outcome that was needed for this indication. We felt like we had an advantage on the technology side. And there is a huge unmet need, as I mentioned earlier. There's no cure today for hepatitis B, and these patients do go on to have lifelong nucleoside analog treatment that still doesn't really completely eliminate their chances for late-stage liver cancer and death. And so it's obviously a huge indication. This is a global disease burden that we really haven't solved yet. And so I think we wanted to employ our technology to try to eliminate cccDNA and inactivate integrated HBV DNA and really provide a complete cure for hepatitis B patients. And so, as I mentioned, we are in the clinic. Our initial data, we've released data for our lowest dose cohort, which was 0.2 milligrams per kilogram, what we were very happy to see. This is actually a repeat administration trial, so each patient gets three administrations, first time that's ever been done with a gene editing approach, and so it was important to establish safety of repeat administration with a gene editor in the liver, so that was very important to see in our first data cut was all patients in cohort one, well tolerated through all three administrations, no greater than grade two AEs, and all of the events that we did see were expected infusion-related reactions consistent with LNP administration. Really excitedly, we also saw antiviral activity in all three patients, and so these patients had different baseline characteristics, including their starting S antigen levels. That's important because other therapeutic approaches have struggled in patients who have high S antigen levels. That wasn't the case for us. We saw substantial S antigen reductions in all three of those patients with really different baseline S antigens. And excitedly, one of those patients actually maintained that durable effect off treatment or after they completed our PBGENE-HBV treatment. And so we're continuing to dose escalate in this study. It'll be exciting to continue to follow the data as it comes out, but we're really excited about the initial data demonstrating good safety and initial antiviral activity in the study. So how do you think about competition from other approaches, including RNAi on one side, epigenetic editing on the other? Yeah, I mean, I think it's simple, actually. We firmly believe the best way to cure hepatitis B is to eliminate cccDNA. And there's not another approach today that does that. Whether it's RNAi, if you're siRNA against or ASOs against S antigen, or epigenetic editing, silencing cccDNA isn't eliminating cccDNA. Leaving cccDNA present always poses the risk of viral reactivation, which we know patients experience. And so we think it's a very differentiated approach and worth pursuing is elimination of cccDNA. Got it, and what is your thinking about the commercial potential in Hep B? Yeah, I mean, it's a huge indication, so there are a lot of patients globally who have hepatitis B. We're starting in a particular subgroup, but it's actually the largest subgroup, so e-antigen negative patients on nucleoside analogs represent about 80% of the population. It's an LNP-based drug, so everybody knows kind of what the cost of goods look like, and especially after COVID vaccines, I think that's a pretty well-established manufacturing pipeline. It is repeat administration, which we think is important to actually achieve cures for hepatitis B, but we think if you can provide a cure for the vast majority of patients living with chronic hepatitis B, it's absolutely commercializable. Great. So maybe coming back to the technology, currently most of the programs that we've talked about here talk about delivery to deliver because obviously there's a lot of expertise to leverage there in terms of delivery, but there's many loss-of-function diseases that affect the muscle, brain, and other tissues. So when do you think we could see progress there, and how are you approaching efforts in that area? Albert, you'll start. So I think liver is the great place to start because of the precedents there. There's clinical validation within the liver. There's a lot of safety that's there. As we start looking into other cells, I think there are different components that you need to evaluate. One is, what is the disease that you're treating? What is the cell type? So are there tools that are available that can edit, but maybe rely on the cell dividing? And so if the cell is not dividing and you need to go, you need to pick a different tool for that. So for example, if you need to go in and do a gene integration, but you don't want to rely on the cell's DNA repair machinery, you probably need to go with something like a recombinase or something that can do that edit in the absence of that. Subsequent to that is just how much do you need and how many of the cells do you need to target? So are there approaches in the CNS that you can get to where maybe you can have a gene and a gene product that is secreted? And so you might target one cell, but can you cross-correct the other cells? It's something that's been established within the enzyme replacement field for many years. Is that possible to do with some of the gene integrations? And then finally, it's really on that safety aspect, what kind of doses? Do you want to get into the CNS by going directly into the CNS? We're seeing a lot of, I think, very positive data coming out on that right now, going into diseases like Huntington's disease, ALS. So there you need a far less amount of drug, and you can point it to exactly where you want. That's probably what you're going to see in the immediate future. And then as we start to develop better tools for targeting different areas with systemic delivery, because you still have to get across that blood-brain barrier for the CNS. So I think there's quite a bit of effort being worked on that aspect as well. Maybe one additional way to think about indications where you need to provide a new protein. Certainly gene integration, gene insertion is one way to consider that. We have a second program internally owned for Duchenne muscular dystrophy that doesn't utilize a gene insertion approach, but actually a gene excision approach where we create two cuts and remove a piece of the mutated gene. And that allows for now proper reading frame reorientation and expression of the dystrophin protein. And so I think thinking creatively about ways to accomplish a gene insertion or, I'm sorry, a gene edit that uses gene insertion or potentially gene excision or other types of edits to actually gain function or gain a protein that is necessary. And then I think you're right, leveraging existing delivery technologies that have clinical validation. So for muscle delivery, AAV has been pretty well established in the gene therapy space to allow for delivery of cargo to muscles. And so we're leveraging AAV delivery for our DMD program. Because our nucleases are small, we can fit two nucleases in a single AAV, keeping that safety margin in mind for AAV to allow for systemic administration, but an excision approach to allow for expression of a protein. Any other thoughts on that front? One thing to mention is that when we look into the indication landscape, what we try to evaluate is whether the integrative gene addition is needed in the first place versus just classic AAV-based gene therapies. And for places like CNS or eye or maybe some of the other organs as well, we're not pursuing those specifically because we're kind of not convinced whether the integrations are necessary in those cases, in addition to kind of the hurdles associated with the delivery to those places. So for tissues like skin, liver, gut, lung, where there is a rapid proliferation of cells, especially if you're treating at a very young age, those tissues are something that are for which the integrative gene addition approach is more compelling, I think. And that's what we're focusing on. And for skin and for liver, there is, as panelists mentioned, there are already existing tools that could be utilized for DNA delivery. Yep, that makes sense. So maybe in the last several minutes, to take several steps back, it's been a fairly volatile year for the genetic medicine space. We've seen some large pharmas limit their activities while others have continued to make investments and even acquisitions in the space. And on the investor side, we've seen some encouraging raises in stocks responding to data or favorable regulatory signals. So from your interactions with investors and perhaps pharma, what is your take on sentiment in the space and what do folks want to see to get excited further? Cassie, we can start with you. Sure. Yeah, I mean, I think clinical data, clinical validation of your technology, signs that you're heading in the right direction for the therapeutic index that's needed for your particular indication. I think a lot of what we've seen on the positive side with investors is on the back of good clinical data and a path towards a future product. And so it's something I really agree with that was mentioned in the last panel too, is having that TPP really clearly outlined and having that end-stage goal in mind from the get-go, I think can give you a clearer path of your development plan and how to get there. And I think investors want to see that clear path, want to see signs of success towards that clear path. And so I think it's an exciting time, especially at Precision with our hepatitis B program yielding clinical data and our DMD program slated to yield clinical data next year. I think that's really been our experience, is later-stage, more mature clinical data, but we are starting to see some of the earlier-stage data be of interest as well. Yeah, I agree with Cassie. I think there's, again, a more cautious approach and as a result, really a desire for more clinical data overall. I think the other aspect is also the commercial model. So people are thinking more longer term and what's the commercial prospects of a particular indication. And I think obviously the greater the commercial potential, the greater the interest. In addition to what has already been said, I think a big area that we've noticed and just in some of the discussions that we've been having is, does it address something that can't be addressed by anything else? And I think that's where a lot of interest lies. So you can have a great technology, does it do something that you just can't do elsewhere? And that's where we've gotten a lot of that interest. Right. One additional item that we are hearing is whether a larger patient population can be addressed by these tools beyond just rare genetic diseases. And the case of Verve and Lilly, I think, highlights that these are the areas where the patient pool is much larger that can excite investors and partners more. Got it. And what are your thoughts on the regulatory outlook for advanced therapies, particularly indications that you guys are pursuing? Yeah, I can start. I mean, I think we've had pretty great interactions with FDA, frankly. I think we've had a pre-IND meeting for our DMD program earlier this year. We've had continued interactions throughout the year on our Hepatitis B program. And anyway, I think what we're seeing is something that Albert said, there's got to be a need for the drug. There's got to be the technology has to have a good reason to be in the therapeutic indication that you're in. And I think we'll continue to see support for drugs that really change the treatment landscape. I think Hepatitis B, chronic infection, that's certainly something that is of interest right now. Providing a cure for something like a long-term infection, we think definitely has support behind it. And then on the other side of our pipeline is Duchenne muscular dystrophy, which has just a huge unmet need. 100% of boys with Duchenne die. And so I think really thinking about choosing the right indication for your technology, I'll come back to that, I think is just really important. I think if you follow that, I think the regulatory path will come. Yeah, I think overall, I've been very impressed with the regulators over a number of years now when it comes to cell and gene therapies. I think they've always, to my impression, has been, and it continues to be regardless of all the noise you may hear, is they continue to lean in. I think that they recognize a significant unmet need and want to try to assist programs in terms of moving forward. There is flexibility, and I think there's also, we're seeing more and more a pragmatic approach to facilitate development, so it's not sort of the old traditional, this is the way we do it and we have to stick to this, but realizing that in smaller populations, one of us has to be flexible and they're open to that, so I'm optimistic in terms of the regulatory outlook. Great. That's encouraging. Albert? Yeah, I mean, and not to expand too much on that, but I do think also the regulators are starting to pave the path for things like the platform designation and things like that that can really help companies as you think about moving forward in particularly in rare disease, and so you're starting to see a lot of movement, a lot of programs that will allow you to get in and really deliver where that unmet need is the highest and make it more straightforward, so moving away from, say, traditional placebo-controlled trials, which is almost impossible for some of these indications. Right, right. I agree 100% on the platform side. And also PRVs play an important role for rare genetic diseases as an avenue for commercialization. So I think that the institution of that would be very valuable for all of us developing rare genetic disease cures. Yeah, absolutely. Right. In the last minute or so, any closing thoughts on where you think the space will evolve in the next few years? Start. I guess I'll start. So I think it will continue to evolve. I think, again, the technologies will evolve. Again, we'll find technologies that work, that don't work. What I'm most optimistic about is, again, these types of approaches where you're editing the genome, we're able to get into populations we never did before, which is young children, where really that will have the greatest societal and economic impact, basically either preventing disease or forestalling the progression of disease before it becomes devastating. So I think this could be a real game changer. Yeah, I think I'll agree with some of the sentiments as well from the last panel that I think over the next several years, we're going to start to see more approvals of gene editing technologies, maybe our first in vivo gene editing approval. And I think as we start to see what that commercial launch and that commercial potential of gene editing therapeutics that I really think can provide transformative therapies for patients, particularly patients that, as Gabe mentioned, haven't had options in the past, I think sometimes I think you think the investors need to see that path forward. And hopefully that will continue to support additional development of gene editing technologies in new areas and new technologies. Great. Albert, Eric. Yeah, two items very quickly. One is going beyond rare diseases into larger patient populations, and two, really reusing the same system to target the same loci with the same enzyme in the case of ARCUS, PCSK9, in our case, other safe harbors, and really applying this technology to multiple indications. Yep. And then the only other thing I'll add on that is, and we heard this from the earlier panel as well, CMC is learning all the time around some of these technologies. And I think the cost of goods are continuing to come down, which then would make it amenable for moving from a very rare local delivery to maybe something that you can think consider for some of the bigger populations. Yep, so efficiencies on CMC and on the platform side can help together. Okay, fantastic, so I think we are at the end of our session, so thank you all again for the great discussion, and thank you guys for listening. Thank you.