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Thank you very much. It's a pleasure to be here. So my name is PJ Brooks. I'm from the National Center for Advancing Translational Sciences. I've been the acting director of the Division of Rare Disease Research Innovation, and I will essentially be acting as the moderator of this session and also one of the discussants. And so what I thought I would first do is have everybody give a brief sort of opening statement about why they're here and their role in this area. And then I'll have a couple of questions that we'll go through, and then we'll have time for audience participation. And just in regard to myself, one of the things I'm most involved with are three large programs, two on AAV gene therapy and one on somatic cell genome editing, all run through the NIH. And they're all based on the idea that we have to get beyond one disease at a time. And, you know, that is basically the title of the talk when I give talks. It's always something like this, because what we're really talking about in many of the diseases are monogenic diseases. And people often say each disease is different, each one is special. And in a way that's true, but at the really basal level of it, the fundamental problem in a monogenic disease is a mutant gene. And if you can put a working copy of that mutant gene into the right cells at the right time and disease progression, something good should happen. And the two ways to do that are gene therapy and gene editing. And so that's the idea between several of these big programs that are running. And that will be somewhat of a theme as we talk about in the discussion today. So let me then give my other speakers a chance to give opening statements. First, Kieran. Sure. I'm Kieran Musunuru. I'm at the University of Pennsylvania. I'm in the Departments of Medicine, Genetics, and Pediatrics. I'm an adult cardiologist by training, and in practice, I take care of patients who tend to be older patients. They tend to have sort of what I think of as garden-variety heart disease, heart attacks, heart failure, rhythm issues, things of that sort. So I'm very much, or at least I started very much the opposite of rare disease. It is, in fact, cardiovascular disease, the leading cause of death worldwide. So it is the exact opposite end of the spectrum. And that's where I focused for many years the earlier part of my career. And when gene editing came on the scene in a big way in 2013 with the advent of CRISPR gene editing, I became very immersed in the idea of using CRISPR to turn off cholesterol genes in the liver. The idea would be I could give you a single treatment. It would permanently reduce your bad cholesterol levels, 50%, 60%, 70%. It would be a one-and-done type treatment, and it would endure for the lifetime. So, it would be like taking a statin every day, but for the rest of your life, and potentially would push off heart attacks, strokes, and diseases like that for years, if not decades. And if you could deploy something like that across a large population, it could increase life expectancy. So, that was my mission for, I would say, the better part of a decade. Developed it in my lab initially, and then spun it out into a company called Virth Therapeutics. They've started clinical trials, and it's been looking very good. have gotten this treatment, and it's all in the clinical trial setting so far, but have had exactly what I was hoping would happen, permanent reductions of cholesterol levels, or at least stable out for two years, but every sign is that it will be for the lifetime. And so as I was sort of wrapping up my involvement in the work, obviously there's a lot more work to do, and I'll go on, and there'll be phase one, two, three clinical trials, and, and there are many companies, other companies jumping into the space, because again, it is the leading cause of death worldwide. I became very interested in the idea. Well, we were able to figure this out, by which I mean turning off cholesterol genes in the liver by using a technology called lipid nanoparticles, which are kind of like soap bubbles. And that carries CRISPR, in this case, a form of CRISPR called a base editor, which can make a single pinpoint change in the genome, one letter into another letter. And we were using that intravenous infusion. It goes straight to the because that's what things tend to do if you put them in the bloodstream. The liver takes them out of the blood because that is its job to clean the blood. And then once in the liver cells, the cargo is released. You have this CRISPR gene editor, this base editor. And with pinpoint accuracy, it finds one of these cholesterol genes and changes exactly one letter in just the right place to flip that gene off. And then that's how you lower cholesterol levels. And it occurred to me, well, if you can use this to turn off a gene by making a pinpoint change, change, we should be able to do exactly the same thing without making many changes to the drug at all, but just aim it to a different place, perhaps a gene that has a misspelling, and use this base editing to correct the misspellings. So to turn on a gene, that was previously off or not working the way it should be. And so this was the summer of 2021, I got together with my close collaborator, Rebecca at Aaron's Nicholas at the Children's Hospital, Philadelphia, across the street from me at CHOP. And we brainstormed that summer and thought, okay, if you could take this basic drug that can go in the liver and make these pinpoint changes, what kind of diseases can we treat? She's a pediatrician. She's physician-scientist like myself, but she's also a pediatricians. And she takes care of patients with metabolic diseases, things like PKU, things urea cycle disorders, things that tend to be centered in the liver, or at least you can potentially make fixes in the liver and greatly improve a patient's health. And I said, let's go. And she said, Let's go, and so we started working on it, and things started to look very, very good in mouse models, and we said, This really has potential, so maybe we can actually apply this to these diseases and correct misspellings. And so we had a goal in mind, which was eventually to get this to patients, but we recognized that, particularly with the sickest patients, those with urea cycle disorders, there are two big challenges. One is that if you're talking about correcting misspellings, with uea cycle disorders, most patients have their own individual misspellungs, you know, these N of one, N of few scenarios, to use that terminology, if that's okay. And so what that would mean is we would have to personalize. We'd have to make bespoke therapies that would correct individuals' misspellINGS. So that's challenge number one. Challenge number two is the question of time. So the kids with neonatal onset urea cycle disorders who are born and then within 24 to 48 hours start to suffer the worst of their disease, which in this case means high ammonia levels in the blood, which is toxic to the brain and has a very, very high infant mortality. So in some cases, greater than 50% mortality in infancy. Devastating disease. And it's not something that you can easily fix. You can do dialysis once and bring the ammonia levels down, but it'll come back up again. the cold, or with the stomach flu, or any sort of stress. And every time they come up, there's the potential for injury to the brain, and so there's a long-term decline. And the only hope for any of these patients has been a liver transplant. But you have to wait till patients are about a year of age, otherwise they can't safely receive the transplant. And so those are the two challenges. We need to make bespoke therapies, but we also needed to do it very, very, very, quickly, within months, if we actually wanted to help a patient avoid the worst consequences of their disease. And so in the laboratory, we started working intensively on making advances and trying to figure out how to speed things up and how to do things efficiently. And one lesson we learned is, can't let perfect be the enemy of good. It has to be just good enough to do something helpful for a patient. And so we were able to take a process that normally would take years and streamline it down to less than a year. So we thought we were doing pretty well. We're starting to get into that window where we might help a patient. And then last August, or I guess two Augusts ago now, time flies, August of 2024, baby named KJ was born at the Hospital of the University of Pennsylvania. Within 48 hours, he became very, very, very sick and an astute physician who was on his care team thought of a urea cycle disorder as a possibility. So did the blood work and found money levels were sky high. That kicked into action, the whole set of things. But one of the more important things taking him in the underground tunnel that connects the hospital of the university of pennsylvania where he's born to the children's hospital philadelphia where he went to the neonatal intensive care unit got dialysis okay fine he made it through the worst of it but it was clear once we got the genetic diagnosis back that he had the worst of the urea cycle disorders condition called cps1 deficiency and the particular misspellings the variants he had were silencing variants nonsense variants which basically killed the the gene entirely. He was making no CPS1 protein at all, which meant he was going to have a very, very, very bad outcome. And he didn't leave the hospital. His only hope was to stay in the hospital long enough and be temporized enough that he could eke it out until he might get a transplant eventually. But when we got the genetic testing results and we looked at the particular variants, the particular misspellings, we realized one of his misspellins was potentially fixable by base editing, the same technology we were using for everything we were doing. and so we said if we can actually show that this works in the laboratory that we can make the correction should we actually try to make the drug and so in a very very short time because at this point we pulled out all the stops within four weeks we we actually realized yes we can in fact correct this variant um and then that that pushed us into reaching out to others because this is a team exercise is not something becca and i could have you know done ourselves in the absence of of help from many, many other people. One of those gentlemen is right here, Sadek, and he'll introduce himself, but he was instrumental in this in getting Danner Corporation and IDT and Aldebaran on board to help to design and manufacture the drug. And then we had academic partners as well. So a pretty large international consortium we did because we did have one company of all that was in Canada. So we'll call it international. All in the service of this child. And we came to an agreement, let's try and do the best we can. And so everyone was wonderful. Everyone said yes, immediately. Everyone was very generous with their time, in kind contributions and whatnot. We just wanted to help. We just want to help KJ. And at that point, Becca, again, she's the pediatrician. I'm not like, you know, this is exactly the opposite of the kind of patient I see. I tend to see 70 year olds who are in, you know, like heart attacks, like that's, you know, that's not me, but she talked to KJ's parents and told them, you didn't know this was going on, but we were thinking about your kid. And, you were doing a little bit of work the laboratory to see whether there was any chance we could help them with this entirely new therapy that no one has ever received before, a bespoke gene editing therapy. Adults have received not bespoke therapies, but this kind of drug, but no infants have. And we actually have assembled a team that if you tell us it's okay, we're willing to try. There are absolutely no guarantees in any of this, but we want you to think about this and you don't have to agree to a trial. This is not a trial situation anyway. You don't, you don'T have to say yes. You're not agreeing to anything, but But if you're open to the idea of this, we'll continue to do our work and whatever happens may happen. And maybe it works out, maybe it doesn't, but we'll try and do the best for you. And they were wonderful. They've been amazing partners from the get-go, from that first conversation with Becca. And they understood that even if we weren't ultimately able to help KJ, that we would learn from this and potentially be able to help kids in the future. And then we embarked on this great adventure and somehow, I'm still not sure exactly how we did. I can't wrap my head around it. Over the next six months, less than six months actually, got the drug made, cleared it with the FDA. We did all the studies that they would normally, not all of the studies, but basic set of studies that they expect us to do, even some animal work. We did as good a job as we could. Again, we're not gonna let perfect be the enemy of good, but as good of package as we can. And the FDA agreed to give it accelerated consideration under the expanded access pathway. We asked them, give us an answer in a week when we filed the IND. They honored that and gave us an answer, a yes, in exactly one week. And then we treated KJ. And we ended up giving three consecutive doses because we wanted to start very, very, very, low because we had no idea what this kind of drug would do for an infant patient. No infant had received it before. Almost a homeopathic dose. So we didn't have much expectation that it would do much, but at least we wanted see if he was safe. And he was sick. He slept through it. He was fine. No big deal at all. But then a remarkable thing happened over the next couple of weeks. We saw that his ammonia levels were very low and we said, oh, this is interesting. Looking pretty good. Let's put some more protein in his diet. So one of the things you do for these patients is you keep them on a very protein-restricted diet because protein is the source of ammonia. It's a breakdown product. And if you can't clear ammonia because you don't have a working urea cycle, then giving you protein is bad. Protein's toxic. You know, you need some protein, so you gotta find that balance, enough to kind of grow, but not so much that it's poisonous to you. So protein-restricted diet, you also give them medication that keeps the ammonia under control. So you're doing these medical things. They're all temporizing. But what we found remarkably was that we would get, we, you know, day by day, 10% more protein, a little bit more protein a little more protein. And he took it like a champ and his ammonia levels stayed normal. And eventually we got him to the point where he was taking a full amount of protein for a child of his age. Like, and he'd never been able to tolerate that before. It was like, oh my gosh, it seems like we did something. And then we started to try to change his medications. But at that point, it seemed that we'd hit the ceilings, like, you know, maybe we had fixed in some of the cells that misspelling, but not all the cells, certainly, or even most of the sales, but enough to give him a little bit of this enzyme activity so that he could take the protein. But that gave, that led us to give a second dose, slightly higher dose, in the hope that maybe we could do better. And in fact, he did, we were able to start weaning down that medication that was, you now, helping to keep the ammonia under control. And then we ended up giving a third dose about a month later. And his ammonia levels after that first dose have never been elevated, despite him having common childhood illnesses, which are the biggest stressor. And after the third dose, we realized that there's no reason for him to be here in the hospital anymore. And no one was seriously entertaining a liver transplanting because he was doing so well. And he'd gone from the ninth percentile of weight for his age, the day before we gave him the first treatment, to more than 40th percentile for his aged, after the third treatment, because he's just gone through this growth spurt. He just soaked up the protein. Just, it just was much, much, much better. And so we treated him before he was seven months of age, a little bit, you know, between six and seven months of age. And right when he was around 10 months of age, he graduated, he went home. And he's been doing great. And I just saw someone showed me a video. KJ and his parents were special guests at the Eagles game. And so we're in a suite and so KJ's out in the public, you know, he's out on the wild looking great. And so it was like, it's very, very nice to see that. Thank you. And so I won't say much more, and we'll have a chance to talk more about this, but you know our goal going forward is, you know we wanna do more of this, but at the same time we recognize that it's not practical to do a lot of these, you know one-off sort of efforts. What we really need to do is do what we did with KJ in a more systematic way, where we're actually trying to learn as much as we can. We need to it in the context of a clinical trial. KJ was clinical care, it was compassionate use of an experimental drug. We learned some things, but what we really to do next is actually set up a clinical, ideally a platform clinical trial where we could treat all sorts of patients with urea cycle disorders. And then get the larger learnings and then eventually be able to move to an approval by the FDA or a platform, if you will. And then once you have the approval, that's the key, because then that's when reimbursement from insurance companies come. And that's, when you make it financially viable and then you can treat all the patients who need to be treated. So I'll leave it at that, turn it over to Sadiq. Great, thanks, Karen. You know, I personally get goosebumps every time I hear this story. And I'll tell you a bit about my background. I'm a Chief Technology Officer of Genomic Medicines at Danaher, a scientist by training. But I got into the rare disease space about 18 years ago when I started my postdoc with Jim Wilson, University of Pennsylvania, worked on the development of an AAB gene therapy for familial hypercholesterolemia, very similar to Kieran's world. But incidence for homozygous FH is one in a million. So really, definition of rare disease. So developed an Aab gene therapy was licensed by Regenexx Bio, but due to the inability to There were creep patients and some of the incentives in the marketplace. The program was shelved, unfortunately. Spent some time in the big pharma space, worked on the development of two of the first Part T therapies that were launched for pediatric ALL and for non-Hodgkin's lymphoma, Kimraya and Yascarda. And I think there's quite a bit of learnings between the rare disease space and the oncology space with regard to advanced therapeutic modalities. And maybe we can discuss some of that during the panel. But then afterwards, spent some time at a couple of different biotechs working on gene editing, one of which was Warbio, before joining Danaher. Danaher is a global life science and diagnostics company. So the company doesn't manufacture therapeutics, but they work with the drug developers, the academic institutions to really enable solutions and development. And we've been in this space for a few years now, thanks in part to the advocacy work of Sharon King, who was at Aldebaran, one of the Danaher operating companies. And one of our first forays as a corporation was with the Spoke Gene Therapy Consortium, which was led by PJ, and really fought for AAV gene therapy across many indications. So we've Been very actively involved with that. And recently, we announced an academic partnership with the Innovative Genomics Institute with Dr. Jennifer Doudna and Fyodor Ernov to platform gene editing for inborn errors of immunity, really ex vivo gene modified cell therapy. So we're making some progress there. But I'll tell you a bit more about the story to elaborate on the baby KJ story and sort of, you know, I think three factors that worked in our favor that we can potentially leverage moving forward. I think, you know, one of the first factors, and, you know, it just happened yesterday, I mean, you know, the call from Karen and Becca and Theodore that happened last year around this time, it was in August when we got the call of can we manufacture this product, and then it was really all systems go. But I think of the three factors that really enabled something like Baby KJ, I'd probably summarize the top three as being the following, and maybe we can open it up during the panel session. I think the first factor that enabled something like Baby KJ to happen was the vision behind the Somatic Cell Gene Editing Consortium that's led by PJ and others, bringing like-minded investigators, really a constellation of data sharing, technology sharing, insight sharing to really enable a collective critical mass in this particular therapeutic modality to advance therapeutic development. And I think that vision enabled the partnership between Karen and Becca and Theodore and some of the other players in the Constellation. I think the second thing that really worked to enable the Baby KJ story was we had all of these technologies available to us. Like none of them were fundamentally new other than maybe the base editor, which was bespoke for Baby KG and then the guide RNA, which is bespoke. But the technology to make these things were all available, but they had never been stitched together in such a fashion under time constraints. But I think the ability to stitch these things together, you know, with the available technologies is probably the second factor that enabled this. And I think the third factor is arguably one of the more important factors is just the deep subject matter expertise of Kieran and Becca in terms of both the disease space, endpoints, what counts, what doesn't in terms of the patient journey, but then also the technical expertise of reducing to practice something from textbook, you know, these are the components to really doing it, you know, with Kieran's experience. And I think if you can scale that, it'll really open the path towards more diseases, sort of that Venn diagram of vision embodied by PJ and the Somatic Cell Gene Editing Consortium, the willingness of the infrastructure embodied by Danaher, Aldebaran, IDT, Acuitas, Jackson Labs, you know, all of the other players that contributed to this, NGH, Broad. plus the deep subject matter expertise and the connection to the patient community represented by Karen and Becca. And I would say those are really the top three factors in sort of reflecting one year afterwards in hindsight of what made it happen. But there are some missing elements, obviously, that I would Say prevent scale up. And maybe we can discuss that during the panel session. Those include the standard things like funding. But I think there are opportunities to really be created, given the precedent that's been set here. And now I'll stop here. Okay, Nick. Thanks, BJ. Thanks very much for having me, and I really appreciate the opportunity to participate in this panel and this discussion. I come to this topic from both a professional and personal perspective on rare disease drug development. Certainly, on the professional side, I've been in drug development for coming on two decades now, the majority of which has been focused on rare disease. As Craig Martin mentioned a couple of panels ago, we've really seen over that time a changing dynamic, make a changing enthusiasm and investment level for industry into the rare disease drug development space. You know, I started out my career along this path at Pfizer, working in the rare disease unit there. I've had the chance today to catch up with a number of fellow veterans of that particular unit, you know, while there, had the opportunity to bring in the first gene therapy into Pfizer through a partnership with SPARC for hemophilia A and B gene therapy program. But, you know, as I think many of you are aware, today that unit does not exist as Pfizer has gotten out of rare disease. From there, I moved on to Roche, had the chance to lead their rare disease unit. I was given the opportunity to participate and play just a small but incredibly rewarding role in the approval for Rizdoplam, the small molecule treatment for spinal muscular atrophy. I had the chance to also lead the acquisition of SPARC and bring that gene therapy technology into a larger pharma. But, you know, as we sit here today, that unit within Roche no longer exists. There's no longer a dedicated rare disease effort. And for all intents and purposes, SPARc has been shut down now, and they've divested that. And they've divested all of their, basically the vast majority of their rare disease assets at this point. From there, and hopefully this isn't a theme, wherever I go this happens, but now from there I got a chance to move on to ASTELLAS, where I headed up the gene therapy research and technical operations team, and got to take part in a number of clinical trials where we were leading gene therapy efforts in rare diseases, got to see the real impact that this has on patients, the real benefit as well as the heartbreak that these kind of programs can generate and the true opportunities that they can present um but you know and thankfully estellas continues to be one of the few companies out there that champion gene therapy are continuing to invest in that but at the same time too they have drastically scaled back their investment in this space so it does speak to this challenge this ongoing challenge we have to how we're going to fund these programs how we're gonna move them forward in a really challenging environment where the dollars are very limited. And that really then transitions to the personal side of my journey and my story here in this space. You know, when my youngest child was two years old, they were diagnosed with Leber's congenital amaurosis due to mutations in the gene RDH12. And, and that launched us on a journey for over a decade and a half to try to produce a gene therapy that could save our child's sight and other children like them. And, you know, it's very heartening and encouraging to hear stories like Baby KJ and to hear that there are opportunities to very quickly move idea to implementation, to be able to quickly move to bring a life-changing therapy to patients. But I would say the more common story for many of us in this space is the one our families went through of just a frustrating story of stops and starts and you know Casey McPherson said in that same earlier panel that one of the biggest challenges we face in rare disease drug discovery is not really the science it's the business model and that that model does not work for us and I think that's that's certainly evidenced by you know some of the history I just went through on the industry side of what the outcome of companies that have actually been successful and delivered life-saving therapies to the market, but also in what we've seen, I've personally seen in my own space, in rare retinal disorders. When you talk about Leber's congenital amaurosis, there's been a lot of success here. The very first approved gene therapy in the U.S. was Leber congenitally amaurosus for RP65 out of SPARC. And following that, we're four for four in additional genetic forms of LCA where it's gone to the clinic and each time they've shown clear efficacy where it's been very clear that these patients, not just that it's saving their sight, it's actually improved sight. That it's had people who are functionally blind, it has restored their vision. But with that comes the frustrating underlying problem in this space. ProQR with an oligonucleotide therapy for CP290 version of LCA. They reported clear signs of efficacy in their trial. But ultimately, when they took that to the FDA, the requirements the FDA placed on them to run a confirmatory trial to eventually get that approved was not fiscally possible under their current situation, and they abandoned that asset. The, their, at SENA Therapeutics, a small gene therapy company in North Carolina ran a phase one trial for Gucin 2D version of LCA. In that report out of that trial, they reported clear signs of improvement in vision. But in that same press release, they also announced that they wouldn't be moving forward with it and be looking for partners to be able to take that on because they did not have the funds to move that forward. AIPL1 gene therapy set within a biotech company that was unwilling to fund a clinical trial because it did not make financial sense for them. So the Moorfields in London were able to get a hold of the asset and ran a compassionate new study, which again established clear efficacy there. But the biotec company that owned the assets was unwilling or unable to fund any further trials. They are trying to get it approved just based on that compassionate use trial data, but they themselves did not put any money into that. Opus Genetics had the fifth LCA program that went into the clinic for LCA5. They too showed in that trial clear improvement in vision, but they were unable to raise any funds around that clinical human data that showed clear benefit, And ultimately, they shut down operations and eventually sold off their remaining assets to a publicly traded company that is trying to take that limited data and get approval just based on that, because there just simply isn't the funding to generate any more data on that. And for our particular version, RDH12-LCA, you know, it's been through multiple biotechs, each one sort of taking a look at it before handing it back to the academics that generated the initial IP, saying that there isn't a business case for it. And just recently, we actually signed, our foundation, our nonprofit foundation, signed an agreement with the reformulated version of Opus Genetics, where we're providing $1.6 million to them to get a clinical trial started on that. And they openly acknowledge that that trial would not be happening, this ongoing, would not be happy without our investment, because they simply do not have the funds to do that. So when we talk about what we need to actually be able to turn all this fantastic science, all this capability, all this clear ability to impact rare disease into treatments that reach patients, it's a need to rethink how we not just fund, but how we actually assemble the data, what kind of data is required, potentially lowering threshold for the dollars required to do that. And that, I think, gets at some of the topics that we're talking about here, potentially in the opportunity to get platform approvals. So in the case of LCA, I've just run through five different trials. Thousands of patients have now received AAV gene therapy through subretinal injections. We have a long history of non-clinical data, clinical safety data that establishes the threshold for the surgical procedure, understanding the safety issues associated with AAV in humans at these doses, and so do we really need the same kind of data packages every time we go back with a new genetic version of these same gene therapies administered through the same route, the same dosages, with the same AAV backbones? Can we think about a combined data package that allows us to just continually change the gene that we're inserting in there with a much more minimal data package to be able to continue to go back and bring these therapies to patients at a much more cost-effective way to really start to make this feasible to bring these things forward. All great points. We've got about nine and a half minutes. We're going to need a bigger boat or more time or whatever, but I know we don't have that. So if people are going to have questions, please stand up because I want to give people a chance. But while you're thinking about that, let's start here. if the rest of the panel has answers to Matthew's questions, because those are really, I had to say, I had similar questions, and you worded it perfectly, and do you have answers? I mean, I think when we're setting up the BGTC and the somatic cell genome editing program, particularly the SMG, we did it in a way that required people to do things and to develop a platform, they were not allowed to do one disease at a time. Whereas the standard business model is to develop a treatment for one disease At a time, you can calculate your return on investment. Scientifically, platform approaches make much more sense, but they apparently don't make sense from a business perspective, and that needs to change. So that's my answer. But why don't you guys respond? So I'll take a different tack. So there's no one single answer that covers all scenarios, right? But I'll give you my admittedly limited, very narrow, very focused answer based on what we are doing. And so I should have said this earlier, and I just, I don't know, being under the bright lights, I just kind of blanked out. But everything that we're doing, notwithstanding very, very kind contributions from Dana and all the other people who are involved with Baby KJ's case, what is empowering everything we are dealing is federal funding from this guy, through the Somatic Cell Genome Editing Consortium. That actually is my name. He's writing us the biggest checks you can imagine. From the NIH, right? And so we're not actually receiving any company money to work on urea cycle disorders. I don't think any company would see personalized editing therapies for urea cycle disorder patients as at all viable, as something worth investing in. And so, we are using the federal funding, public funding, to take the work forward. And so, you know, this gets to the idea that we've already mentioned a few times, platforms, right? How do you extend what we did with a single patient to many patients? And I told you earlier, part of the answer is you have to get to clinical trials because that's so important because that is what makes something approvable. But I think you can do some creative things. So you have to get out of this mentality that there's a single version, single drug that has to go for every single patient. Think there's, there's an, there is a drug entity, you want to use that term, that can broadly serve a large number of patients with some degree of personalization. And right, so I talked about gene editing. It turns out that if you want to get CRISPR or a base editor to go to somewhere else, to go into another gene versus this other gene, all you have do is change one component of the system. Otherwise the drug is exactly the same. The fatty spheres, the soap bubble that carries the cargo is the same, the editor itself is by and large the same the only thing you're changing is one small piece that you can almost think of as a GPS just says go to gene A, that will turn off a cholesterol gene versus gene B that will fix the misspelling in the gene. And so if all you have to do is change that one small peace then it's just a question of convincing a regulatory agency like the FDA, hey, it's all the same drug. And CRISPR-based editors, they're agnostic to disease. They, you know, I'm anthropomorphizing too much, but they'll just go where you tell them to go. It doesn't matter what disease you have. It doesn' matter if it's PKU or hypercholesterolemia or urea cyclodysauria or whatnot. It goes where you aim it. And so why do we impose these boundaries of disease on a technology that is disease agnostic, right? And so we're engaging with the FDA, trying to push this concept. And so where we're starting is with urea cycle disorders and said, you know, there are gonna be different variants. If the same editor can correct the misspellings across a group of patients, let us include them all in what we call an umbrella clinical trial. We make bespoke versions of the therapies for them. But we actually didn't stop there. We said, we're not stopping with one disease, like one particular urea cycling disorder. We want all seven urea cyclo disorders. Let us include any patient with any urea cycled disorder with a variant that we can correct in an umbrella clinical trial. And then you could extrapolate beyond it. It says, well, as long as it's something in the liver that you can fix, like why do you have to restrict yourself to urea-cycloid disorders? It could be the whole universe of disease. Now, we haven't pushed them quite that far yet. That will come someday. But we're starting with the urea cycloid disorder. We'll actually found out next week. We have a pre-IND meeting next week and we'll see exactly what they say to that concept. Stay tuned. But the other exciting part of this is just yesterday, there was an article that came out at Endpoints that sort of, I think, was actually a bit of a scoop, I guess. I don't think it was intended to come out quite yet. But it seems that inspired by Baby KJ's case, the FDA is seriously considering a bespoke pathway where if you actually have a drug entity where you're personalizing, this version for patient one, this version for patient two, so basically five different patients like KJ, each with their own misspellings and you're making these two versions, but it's basically the same drug. Then with as few as five patients treated and shown that this drug is safe and this drug seems to be working by some objective criteria, with as fewer as five patients, the FDA will consider a conditional approval. Five patients, a conditional approval. And again, that approval is the key because then you can and then seek reimbursement from insurance companies. And that makes it fiscally viable. And so I'm happy to say that with all the generous funding from PJ, we actually are resourced to be able to potentially do a clinical trial with five patients across the recycled disorders and take it all the way, if that's really what it takes, just five patients, actually do it all, take it the way to approval. And then what happens after that? I have no idea. Like, is it an academic center that's actually holding the approval and actually like the marketing authorization and then is somehow like responsible for the drug. I guess that's what happened. I guess, and at least with rare and ultra rare diseases, maybe that's, what has to happen. It goes away from companies and becomes centered in the academic center. And then, you know, it's, you what I like to think of as interventional geneticists and new cohort of physicians who are trained to think about these therapies and work with these therapies and treat patients with these therapy. Maybe they're the ones, they're more like surgeons, right? And then Danner, IDT, Aldebaran, they are the suppliers. So instead of a surgeon getting a scalpel, getting a retractor, getting drapes, it becomes an interventional geneticist getting an mRNA and a guide RNA and then getting assembled into these lipid nanoparticles, these soap bubbles. And then it's the interventional genetics who is responsible for actually treating the patient, managing the patient, and so forth. So it becomes a very academic slash hospital-centered model to treating these rare diseases, where where companies are probably never going to be perfectly honest. I just want to give out two comments. Sorry. I get two in this, yes. No, I would agree. I mean, I think because a lot of times people think that manufacturing is the rate-limiting step in terms of cost. I think if you look at the line item, manufacturing is definitely, you know, I mean it's not insignificant, but I think it's really the innovative clinical trial pathways that we're seeing out of academia, the investigator-initiated trials that are really pushing the boundaries of what can be done that I haven't seen within biotech or pharma. Like what Karen is talking about, that innovative clinical development path really needs to be enabled and incentivized. And then I think reimbursement, if we can get to that surgical procedure reimbursement model mindset, which it seems like CMS is open to, but it's just showing more proof of concept. So I would agree with everything, and just with a caveat that oftentimes people think manufacturing is the rate-limiting step, but I would argue that it's the clinical development pathway that people take. It's not aggressive enough. So I do want to pick up on a couple of things that Karen mentioned here. I think, too, so yes, it's fantastic that our current government research environment is able to support things like that. Also, though, I do recognize that those dollars are starting to get scarcer and scarcer as well. And that just, again, creates a potential problem where whenever the industry fails to do that, and then also potentially government is not there as well, it really does call out for a new model. And that's where I think the other thing that you're saying there, Kieran, I completely agree with, that ultimately, I think both the need and the real opportunity for true innovation is for a New Kind of company to come around to really, or not company, but entity. Entity, that's a good way, yeah. These kind of therapies available, because the reality that we're seeing already, even with some of the approved ones that grew up and started in big pharma is that's not going to be the long-term home for them. I can tell you, I know of a couple of these approved assets that companies are trying to find new homes for because they no longer make financial sense for them to support. Particularly in gene therapy, where when you talk about from a revenue perspective, all of the revenue is in those first couple of years when you treat the prevalent population. Past that, and you're just talking about new births, new patients, the incident population, the economics for larger pharma no longer fit. But yet for a small purpose-built organization, those kind of just reimbursement plus type models could be enough to both sustain the availability of these treatments back to patients, but also to help fund new therapies coming through, which I know I see Craig's one because I think that's his thinking. I think there's a lot of that, but there just hasn't been enough energy or support or even, yeah, I guess really support around that to make one of these sort of things stand up. But eventually, it's going to have to coalesce around a couple of these kind of organizations long term because I Think ultimately, our system is showing that the status quo isn't Bill, provide these kind of therapies to patients. It looks like I've got a lot of time here. We have one more question. I've been super patient. I have a really similar experience to Matthew with programs, you know, getting incredible results, showing incredible efficacy. And then commercial viability means that these programs get dropped and given back to academia. You can hear from my accent. I'm from the UK. And actually, we have, we are working on a model where we're trying to take ASOs and separately do therapies through to these basket type approaches. One of the main issues that we've come up against, because we're doing this in the UK, in Europe and in the US, from the US perspective, we've had regulators agree from the CMC perspective that, you know, yes, you're making these small changes. And, you Know, the CRISPR technologies are very, it's almost identical. It's like a device. I think Peter Marks described it as a medical device where essentially you're making a tiny change to the end of a scalpel and therefore, you know, we should only really be looking at that. The pushback we've had, so I've been in FDA meetings with several biotechs who are trying to do this umbrella or platform approach across lysosomal storage disorders, across ureous cycle disorders, and the feedback we consistently get is from the clinical team, this is not okay, you can't do this. we have to look at these diseases individually and therefore these programs never go forwards because the commercial funding isn't there and I do think there is a business model commercially for platform approaches because it gives you wider access to a larger patient population but I do Think that I've seen a regulatory pushback so I'd be interested in hearing about your more recent discussions of FDA because I was having success last year that's not happening anymore. But I'm, you know, I just don't know how we overcome those regulatory barriers. And there's just no appetite for investment in that space if the regulators aren't going to agree and approve. Well, my short, very short answer to that is it does seem like opinions are changing at the agency that the FDA is showing a lot more openness now to, you know, being flexible when it comes to particularly rare, ultra rare diseases and being willing to take on more platform approaches and thinking more creatively about what would the approved drug label look like, right? Because it wouldn't be a traditional drug label. And at the end of the day, that's what they care about. You're approving something. What does that label actually say? And so that's where the flexibility really needs to be. Is it a very, very narrow, like this single drug for this disease, or you can have more expansive labels? And from discussions I've personally had with the FDA, both formally and informally, and just my colleagues. And the sense we're getting is that there's much more openness to this, which is obviously a very, very positive sign. I'll say, yeah, I think right now there is a lot of uncertainty. I can tell you we had a fairly recent interaction with the USDA around what kind of data package we could bring and get and to be able to open an IND, really positive, really showed a lot of flexibility. But then within a couple of months, all the people that we talked to are gone. So the thing is, is the current administration, I think we've heard a lot of positive sentiments from them about changing the dynamics here to really be supportive of rare disease drug discovery. And so I take that as encouraging that some of the innovations, some of the reforms that have been initiated under previous administrations are going to be continued and potentially advanced. We're just going to have to wait and see how that ultimately plays out as we see the new administration really put its policies into work. All right. Any other questions? All right, thank you. Thank you all.