All right, can you hear me? Very good. I think you can, right? We're a webcast, so I'm gonna go ahead and get this going. First of all, thank you for coming over on a beautiful New York spring morning to spend a little bit of time with us, and thank you to everybody who's joined us on the webcast as well. Our goal today is relatively straightforward. We're really optimistic that we have the potential to build a meaningful and durable company that has impact on tens of thousands of patients per year and creates value really for all of our stakeholders. What we're gonna try to accomplish today is three things. One is to tell you a little bit about why we're so excited about where we're going and what some of the areas are that we're going into. The second is how we think we're gonna learn, in the very near term in many cases, whether or not we're on the right track, and to really help you to understand how we see risk changing and where we see changes in how we'll think about allocating capital and investing and moving forward. The third is to introduce you to some of the people who will be really instrumental in ensuring that we can both leverage the opportunities that sit in front of us and also navigate the inevitable challenges that will come with it. It's pretty straightforward. Hopefully we'll get that done. To do that, of course, we'll have to make some forward-looking statements. We spent a lot of time writing our risk factors. Take a look at our 10-Q, which is on file with the SEC. There's a lot of information in there. When we started the company, our goal was really to turn engineered cells, the power of cellular therapy and gene therapy into a reality. It's a reality that hopefully is accessible for, you know, tens of thousands of patients or hundreds of thousands of people per year. In doing that, we've really built four platforms over the last several years. One is what we call hypoimmune modified cells, an ability hopefully to hide cells from immune recognition and allogeneic and autoimmune rejection. The second is to be able to scale this, we have to be able to make things repeatedly, and we've built capabilities around stem cells that we think can be very, very valuable. The third is we don't just wanna replace cells, we actually wanna repair them in the body when at the right time. To do that, I think most of you recognize you can do almost anything you want to a gene inside of a, in a Petri dish, in a lab, and the real challenge has been in vivo delivery. We'll tell you a little bit about our fusogen take capabilities, which are geared towards in vivo delivery. Once we get to the cell, we don't just wanna randomly do things. We wanna be able to deliver really any payload and to be able to modify a specific gene in a specific cell. We call that genome modification, and we'll show you some data of the progress we've made around that. We're making progress across all four of these areas and it will be fun to share that with you. The most near term, though, is our hypoimmune platform, where we are optimistic we'll have proof of concept from two different studies as we move through the rest of this year, hopefully showing that this platform really does work as we hope it does. First is a drug called SC291. This is a gene-modified, allogeneic CAR T-cell targeting CD19, that we're moving forward in B-cell malignancies. We'll tell you a little bit about that and how we see success, shortly. The other is a gene-modified, islet cell, which can go into Type 1 diabetes. If we're successful with that, I think our view is that all the component parts have come together where you can now comfortably say that a cure for Type 1 diabetes is inevitable. Right now it's possible, but it will really change it to inevitable. We won't be done, if those things do play out as we hope. We not only go after CD19 and Type 1 diabetes, but our allogeneic CAR T-cell field, we've got SC262, hopefully with an IND later this year, and SC255. Those target CD22 and BCMA respectively. We'll tell you a little bit about why we're so excited about the opportunity in autoimmune disorders, as part of that, we have both the scale to do this and actually the drug products in our shelf to move quickly, and we think it can be a really important part of the company. I talked about SC451 already, which is type 1 diabetes. Finally, we're gonna talk a little about some things we haven't talked about before. One is SC379, which is a glial progenitor cell drug, we think that can be really quite disruptive in the treatment of CNS diseases and some of the progress that we've made in moving forward with our Fusogen platform, both with SG299, which is a CD19 CAR, and also with delivering specific gene editing payloads to specific cells inside the body. That's a little bit about who we are and where we are. There's a lot of stuff coming in the very near term. Just to start, transplant rejection has been a huge problem ever since the advent of transplant medicine. It's true whether you're looking at solid organ tumors or bone marrow transplants. The field has really struggled with how to deal with this. Immunosuppression has been helpful, but it's, one, very toxic for many patients, they end up with infections or cancers, and two, it's not tolerated that well, and that's really limited the field. Others have tried going down the path of autologous cells. That has worked somewhat. It's difficult to scale, and of course, it's only usable in a very small number of cell types, cells that exist in suspension, bone marrow cells, T-cells, things like that. Our goal has been to really design a platform that will overcome the immune rejection of foreign cells, we think if we can do that, you have a just a vast array of opportunities ahead of us. The way we went about it was, first and foremost, was not to approach this randomly, but to hire a team of really great transplant immunologists who understood the challenges ahead in the field. The real key has been that you have to overcome both adaptive immunity and innate immunity. Adaptive immunity, which is our B and T cells, is relatively easy to deal with, and the field figured this out a while ago. The challenge has really been trying to figure out how do you deal with the innate immune system, in particular NK cells? Our team's been at this for a while, and I have to say they pioneered a lot in the field. We have foundational intellectual property that goes back almost a decade. These are just some of the high-quality papers that have been published from this group, including three over the last six weeks or so in science and Nature journals, where they really, I think, begun to untangle the web of what is this challenge around immune rejection. We'll share some of that data with you, and we'll also share some new data with you. This is just an example of some things we haven't shown before, and this is a non-human primate model of diabetes, where we've shown that we can transplant cells and the animal will be euglycemic with no immunosuppression, despite the transplant of allogeneic cells. We're very excited about where we can go in diabetes. We've now gone and you'll see more of that data later. If we've shown that we can overcome allogeneic rejection in mice, in humanized mice, in non-human primates. We've done this across multiple cell types. We've done this in multiple geographies. In fact, we've done over 40 non-human primate studies just to understand this. I would postulate to you that if you were a mouse or a mouse with a human immune system or a non-human primate, the problem of allogeneic rejection would be solved. Of course, none of us are, right? The real challenge is can we do that in people? If we have, just in near-term opportunities where others in the field have already validated the biology, have already shown you that you can transplant cells and have potentially curative effects, we get the opportunity to go after a host of different diseases. In blood cancers, over 100,000 patients per year are still dying of diseases that are readily addressable by CAR T cells. Autoimmune disorders, you know, you could argue that you have over 5 million patients that suffer from diseases where there is clear proof of concept that B cell depletion, and not just B cell depletion, but better B cell depletion, will lead to increased effect. Type 1 diabetes, which already has shown some, you know, the effect of transplanting cells with immune suppression. Those are big, big opportunities that sit in front of us, and all of them have very near-term proof of concept. To understand the proof of concept and where it's coming from, I'll just take a step back and make sure you understand our medicines. The first place we took the Hypoimmune Platform was in allogeneic CAR T-cells. What we do is take a donor, a healthy donor's, white blood cells, take out their T-cells, gene modify it in ways that we'll describe in more detail later, and insert a CAR, which will allow it to recognize and then kill the cancer. We can do this across multiple different targets. The first drug, it's CD19. All right? When you do that, you actually end up with a bit of a mixture of fully edited cells and not fully edited cells. In fact, only about 40 to 50% of cells have all of the edits that we need to hide them from the immune system. That sounds like a bug, but in translational sciences, we can turn it into a feature. When a patient gets CAR T cells, the first thing they do is they get lymphodepletion, right? It's an autologous CAR T cell. That will knock down the immune system, but it's pretty gentle, and it comes back relatively quickly within a few weeks. What we see, you know, consistently with, you know, most strategies with allogeneic CAR T cells is they're gone within 2 to 4 weeks as the immune system recovers, right? People have tried to just knock the immune system down more robustly. If here what you'll see is we'll knock the immune system down, it'll come back within two to four weeks, and as the NK cells recover first, which they come first, and then the T cells, you will eliminate all of the cells that aren't a 100% edited. At the end, if things work like we think they will, you'll have basically a 100% of the remaining CAR T cells will be fully edited. You'll know probably at 1 month if all you see is CAR T-cells, definitely at 2 months, you know, definitively at 3 months, if it's 100% CAR T-cells, that we have actually overcome the challenge of immune rejection and that all of that data that you've seen in mice, humanized mice, non-human primates will translate into humans. That opens up a huge array of opportunities for the company. It doesn't mean we have a drug, right? What it will mean is that we have solved this biology problem, and now we need to turn it into medicines. The way you turn it into medicines is keep peeling back the evidence. We'll have immune evasion data. You know, we can figure that out very quickly within a few patients. You know, we'll do that. We have an ongoing, you know, enrolling study called ARDENT, which we'll talk about for the CD19 CAR. If you have immune evasion and you see cancer cells killed and now they persist, that should lead to durable complete responses. We will know early evidence of, you know, just the complete responses and persistence, again, as we move through this year and into next. The durable complete response is 6 months and out, you know, functional cures. Hopefully, we can begin to see that as we move into next year. Our goal is very simple. We want allogeneic cells that behave at least as well as autologous cells. We're not trying to make them kinda good. It won't be success. We want them to work at least as well as autologous cells. We have reasons to believe that they could be better. Terry's going to walk you through, because sometimes I hear from some investors, they're a little confused about whether or not cellular persistence really matters, which is, you know, it's a hard argument to make that area under the curve of your, of your active pharmaceutical ingredient isn't important. We'll show you a lot of data from the CAR T-cell field that that's that backs that up. If it works in CD19, as I mentioned, we won't be done. We will be moving into CD22. We'll be moving into BCMA. In both cases, we have CAR T-cells with what looks like best-in-class data in the autologous CAR T-cell setting. As you move that into our platform, it's a very low biology risk to making three different medicines. We have a host of targets to go forward. To remind you of what this really means, you have data already and approvals already in multiple lines of therapy in lymphoma, myeloma, leukemia. What we've seen is that patients still cannot get drug. If you went over to Memorial Sloan Kettering and asked them what percentage of their patients can get a BCMA CAR T-cell today for myeloma, they would say it's one or two out of 10, right? It's just nowhere near where it is. That's before you move into those light blue circles of expanded indications. On the right, you see 250,000 people in the US and Europe get these diseases every year, where you have clear definitive proof of concept. Over 100,000 people die every year. Last year, just over 10,000 people got a CAR T-cell. Of those, you know, only 30 to 40% have really benefited. Our goal is to take that little blue circle and expand it so that that big blue-gray circle becomes a whole lot smaller at the end of the day, and it's right in front of us. We won't be done. You know, for a while, for the last 25 years, the field has been trying to figure out how do we deplete B-cells, and when you do, where can you have benefit for patients? Not only has it been important in cancers, but it's also been shown across a host of different diseases to be highly impactful in autoimmune disorders. I'm sure many of you have seen the data from an autologous CAR T-cell as an example, you know, from Germany, over the, you know, the last year or so. We'll go into that in more depth later. One of the things that's been shown is that the depth of B-cell depletion correlates directly with both the depth of response and the durability of that response. With that autologous CAR T data, what we've seen is the potential for people to have durable long-term remissions off all therapies or maybe even curative. You could see that CAR T-cells could do for autoimmune diseases what they have done in blood cancers. To do that, you can't manufacture drugs at scale that won't even at a level that won't even meet demand for third-line cancers. You have to fundamentally change the way you approach the CAR T manufacturing. We already have the scale to move forward here. We make what is likely the autoimmune dose almost 1,000 batches for dosing per manufacturing run. That means if you have 100 runs per year, you can treat 100,000 patients, right? It's totally transformative. We have the drug product from our oncology study sitting on our shelves, right, ready to go. This is something where you're gonna see us move very quickly. Doug Williams will outline this for you, and where you can see proof of concept across multiple studies from something like multiple settings, I should say, from something like a basket study in the near term. Stay tuned. I think this is gonna be a really exciting area for the field. If we truly have what we think we do, which is an allogeneic cell that performs at least as well as an autologous cell, we'll be in a great position to really go after that. Of course, we won't be done. Stem cell therapies are. We wanna move away from these donor-derived therapies into stem cell based therapies. We have a single cell that becomes your entire drug product. It's very scalable and reproducible. type 1 diabetes is simply put a disease of the immune system and the beta cell, right? Your immune system kills your beta cells. The field has shown that if you replace beta cells and immunosuppress a patient, you can have a patient who is functionally cured. Our goal is really simple, which is to make from a stem cell a product where a patient will be euglycemic, normal glucoses, with no immunosuppression and no insulin, and to have that last for years and years and years and years and years. We'll have an IND from that product in the near term. We're also looking to take stem cells into glial cells, this is an area many of you probably don't know as much about, we'll spend more time on basic biology. They're implicated in the majority of CNS diseases. Glial progenitor cells are bipotent in your brain. They can become either astrocytes or oligodendrocytes, and they target diseases of hundreds of thousands of patients. We have an opportunity to move forward with an IND next year and really go after both rare genetic disorders where you have the opportunity to get the clear proof of concept early, as well as very large and prevalent diseases that affect, you know, people that we all know, you know, like progressive multiple sclerosis or Huntington's disease. Steve Goldman will tell you a little bit about those later. We have a chance in the near term in diabetes for another proof of concept. The idea here, patients have been getting primary cadaveric islet transplants in the hundreds per year for well over a decade. They work to keep patients off insulin for long periods of time, but they have to be heavily immunosuppressed. The demand for them hasn't been that great because there aren't that many people for whom lifelong immunosuppression is better than lifelong insulin. Our goal through an investigator-sponsored trial is to take these cadaveric islet cells, introduce our gene modifications to make them hypoimmune, and transplant into a type 1 diabetes patient without immunosuppression. You will know if you can transplant cells within a week or two. A regular allogeneic cell would be rejected. If these cells are alive at 2, 3, 4 weeks, let alone at 1 and 2 and 3 months, again, we'll have proven that we can overcome the barriers of immune rejection in the allogeneic setting, and we've also shown at least in one autoimmune setting that we can do this. This is an opportunity for us to get rapid learnings around how our platform is really performing, and we'll get into kind of how we define success and key measures outcome. If you were really excited, you start with a lower dose. We're looking for cell survival and C-peptide, which is a measure of insulin production. If we happen to have glycemic control, we'll be doing cartwheels, particularly for that patient. That all sits in front of us, and that's all stuff we're doing where we're replacing cells. That's not all we wanna do. We wanna be able to fix cells in vivo as well, and we have this program, we call them fusogens, which allow cell-specific delivery, and we put them into something called a fusosome, right? Which is like a... Think of it like a virus-like particle where you've got both targeting and you can put packaging in it. What we're gonna show you is that we can do cell-specific delivery, and hopefully we'll have an opportunity to prove that in humans with an IND slated for later this year with SG299. And that we can deliver diverse payloads, and those include things like typical nucleases used for gene editing. They include base editing. This is just an example we'll go into, and it's a whole lot more that we can do with these. They're quite powerful tools that are able to really think about this change any cell gene in your body in a specific cell. That's the goal. That allows you to get more potency and efficiency. It allows you to have much more safety, 'cause most of your drug product, if it's nonspecific, will go into non-target cells, and it actually allows it to be scalable because if 90% of your drug is going to liver and 9% of it's going to some other cell and 1%'s getting to your target, you have to manufacture a lot of drug to have the impact. This is better efficacy, better safety, and better manufacturability if we get it right. That's basically what we're gonna talk to you about today. These are INDs this year and next. This is not the full platform. You can see we've got a lot of activity inside the company. We have a lot of opportunities for clinical data over the very near term, let's call it next couple of quarters and as we move through next year, and we're quite excited to tell you about some of what that is. The people you're gonna meet today, just as a way, the... We've kind of built the company by trying to put together two types of people, the really creative, innovative scientists that have been thriving in academia with the really drug hunters and people who know how to turn innovation into drugs that sit inside of industry, and you'll meet a little bit of both of them. Sonja Schrepfer runs our hypoimmune platform. She was formerly a transplant immunology professor at UCSF. Terry Fry runs our T-cell as a therapeutic platform. Terry had formerly ran the T-cell program, cell therapy programs at the National Cancer Institute and has been at the University of Colorado as well. Doug Williams, for those of you who don't know him, has been really someone who has been a leader in research for over 2 decades in our field, has played a large part in building companies like Immunex, Seattle Genetics, Biogen Idec, and has been developing immunology drugs in particular through that whole time, including multiple blockbusters. Steve Goldman is someone who's been leading the field in glial biology and is a real thought leader as well in how things work with stem cells and turning stem cells into controllable medicines. Ed Rebar, who you'll meet, is someone who's been in the gene editing field since its inception in the late 1990s and understands not just how to gene edit, but how to turn genetic reagents into real medicines. I think that's something that hasn't always been straightforward. I almost forgot Richard Mulligan. If you don't know Richard, he's someone who ran the Harvard Gene Therapy Initiative, made many of the fundamental discoveries that allowed viruses to be used to deliver genes. He has been a part of the core of our scientific team since the outset of the company. The last person who's not here, but will be available for Q&A is Gary Meininger, our Chief Medical Officer, who recently joined us from Vertex, where he ran their cell and gene therapy clinical development. Those are the people you're gonna meet today. Hopefully you'll be, you'll have a chance to learn a little bit more about us and to share some of our excitement about what we can do. With that, I'm gonna turn it over to Sonja. Thank you, Steve. Thank you, Steve. I'm happy to show you today some details about the hypoimmune platform. On this slide, what you see is Christiaan Barnard, and I met him when I was in school because my background is in solid organ transplantation. Christiaan Barnard transplanted 55 years ago, the first heart into a human being. I show you that slide because you see the patient, Louis Washkansky, on those pictures right after the surgery, and he looks quite happy and well. However, the immunology kicked in a few days after the transplantation, and Louis Washkansky was immunosuppressed, meaning he had to take medication to dampen the immune response that he wouldn't reject the transplanted organ. Immunosuppression is every day a struggle because if we give too much immunosuppression, the patient has a risk of infection, malignancies, toxicities on kidney, liver, other organs. If we don't give enough immunosuppression, the patient has the risk of rejecting the transplant. Back then the surgical team thought that he would need more immunosuppression. They increased the immunosuppression, unfortunately, Louis Washkansky died on the 18th postoperative day. That shows you really the struggle we have in the field for not only solid organ transplantation, but cell and tissue transplantation. For cellular transplantation, of course, we do have the option to transplant autologous, meaning that the cells come from the patient, and then we transplant the very same cells back into the same patient. That wouldn't lead to immune rejection. There is struggle with manufacturing and of course, there's the access limitation that not every patient has the possibility to access those therapies. What you see on the right side of that slide is the allogeneic cellular therapies, and the idea is that we have a healthy donor, and we could generate multiple doses for many different patients really off the shelf for anyone, anywhere, anytime. The problem is when we think about allogeneic transplantation, that the graft or the cells we are transplanting are subject of immune rejection, and the patient would need immunosuppression. I want to show you how we thought about how can we overcome this allogeneic barrier, meaning the vision transplanting cells without the need of immunosuppression. We learned from nature, because during pregnancy, the fetus is expressing 50% of the proteins from the father, but the mother's immune system is not rejecting the fetus, although the immune system recognizes the fetus as allogeneic. What you see here on the right side is that Sana's hypoimmune approach leverages that knowledge, and we are using an healthy donor cell. The first thing we try to overcome an adaptive immune response, meaning T cells, B cell response, antibodies, is that we are wiping off this fingerprint on the cells, and the fingerprint, those are the MHC or HLA molecules. By doing that, the T cells are not seeing the transplanted cells, so you can easily overcome that adaptive immune barrier. Because we are creating that cell, that missing self, there is no fingerprint on the surface, innate immune cells, NK cells and macrophages, they are sensing the missing self, and they are killing. We had to overcome this innate immune barrier as well. We show you data today that we are overexpressing the CD47 molecule. That's a "don't kill me" molecule, and we can overcome that killing by innate immune cells. When we started in the field, you see the histology picture, all those purple dots, those are immune cells. That's how it looks like when a graft gets rejected. When we then studied the feto-maternal border, where we know the fetus is not rejected by the mother, we saw that there are certain molecules overexpressed or downregulated on that feto-maternal border. We studied each of those molecules alone and how that molecule affects the adaptive and the innate immune system. Then we came up with a list you see on the right, where we then started to think, what is the minimum amount of molecules we need to combine to achieve an hypoimmune cell product? As Steve already said, wiping off the MHC molecules, the field is recognizing that you can overcome the T-cell response with that. The goal was really then how can we protect the cells from the innate immunity? We studied certain molecules, and I want to show you a few of them, where you see in the gray boxes the molecules we are studying. Those molecules, when you overexpress that on your cell transplant, what they do need is the corresponding receptor on the NK cells. It's like a key and lock principle. If you overexpress the molecule, of course, it has to find its receptor on the NK cells. The issue with the NK cells is what you see on that slide in the flow plots. For example, I use the HLA-E to show you that the receptor CD94 is only expressed on 28% of the NK cells, meaning you're not able to inhibit the overall primary NK cell population. For the PD-L1, you see the example here, only 3% of NK cells are expressing the receptor, the PD-1. When you look at those flows, you see that CD47, the receptor SIRPα, is expressed on all NK cell subpopulation. That leads to the protection of the cells that they are not killed by NK cells. What the videos here will show you are in green the target cells. We have a missing self cell, and then we overexpress the molecules HLA-C, E, G, PD-L1, PVR was a knockout of CD47, and added NK cells. What you see in those videos is that over time, because not all of the NK cells are expressing the receptor for those molecules, NK cells are killing the target cells. You see that the CD47 is a total protection because the receptor is expressed on all NK cells. I always get the question when I go on meetings and share those data, "Oh, could you combine those molecules? Is it maybe an additive effect, and you just combine three or four of them, and then you get protection? I wanted to show you these videos where we played around, combined certain molecules, and what you see is that even with combination, there is no such thing like an additive effect of those receptors on NK cells, meaning that the single overexpression of CD47 is protective because the receptor is 100% expressed on the NK cells. What we started is that we wanted to have an allogeneic model and mouse model. We created induced pluripotent stem cells, iPSCs, from BL6 mice, and then we transplanted them on the bottom row. I see if the pointer is working here. The bottom row into BL6 mice. There is no immune response, but when we transplant those cells into the allogeneic BALB/c in gray, you see that the gray graph is much higher than the blue. This is T-cell activation. The other graph shows you the IgM antibody binding. We then induce the hypoimmune edits, so MHC class one, class two knockout, CD47 overexpression, you see that the gray and the blue are at a similar height. That shows you that we were able to overcome that adaptive immune barrier. What we show you here on the right side is that wild-type cells don't get killed by NK cells, so the line here is up. We are disrupting the MHC class one, class two molecules, and we have the knockout, you see the NK cells are killing. We overexpress CD47, now the line stays up again. That shows you the protection of that CD47 molecule from the NK cell killing. We then moved on, and we wanted to use a more translational model. We choose the non-human primate model, the NHP model. I show you data here from eight NHPs. In group one, we first transplanted unmodified allogeneic iPSCs from one NHP into another. After six weeks, we then did a crossover experiment where the very same NHPs received an hypoimmune transplant. In group two, it's a vice versa experiment. We first transplanted hypoimmune iPSCs. Six weeks later, we transplanted the wild type, and then we did immune studies and surviving studies. What you see here is the transplanted cells were labeled. We could follow them in vivo. Group A is the transplant of first hypoimmune iPSCs into the left leg muscle of the NHPs. After 16 weeks, you see here the image, and you see in blue the line, how it stays up. Those iPSCs were able to survive in the NHP without immunosuppression. After 6 weeks, we had transplanted the unmodified wild types into the other leg muscle. That's what you see in the 2nd row and in gray here. You see that the unmodified iPSCs are rejected quite fast. What those data show you is this is a concept of immune evasion. Although the immune system rejects now the unmodified iPSCs, you see that the hypoimmune cells are surviving because the immune system is not seeing them. They're evading the immune recognition. In B, you see the transplant of first unmodified iPSCs. As expected, they get rejected quite fast within 2 weeks. That's a normal allogeneic response. 6 weeks later, you see that we transplanted hypoimmune, and those hypoimmune cells are surviving. That shows you that hypoimmune cells can be transplanted into sensitized recipients because the immune system of those NHPs knows the antigen but is not seeing the hypoimmune cells after transplantation, and therefore they are surviving. We did a bunch of immune analysis, and I want to show you the upper row first, the unmodified NHPs. The gray bars are the injections of the wild-type iPSCs, and what you see is in the T-cell activation, high gray bars in the beginning, like 1 week after the transplant, and then it declines over time after the cells are rejected. After 6 weeks, you see in blue there is no bar graph, so there is no T-cell activation against the hypoimmune. If you look at the IgM antibody production, there is no de novo antibody production. After the unmodified transplantation, we see first IgM antibodies and then the switch to IgGs. I like to show the slides because that is normally what we expect in patients, and it underlines how similar the NHP immune system is to the patient's immune system. What you see on the bottom is we first transplanted hypoimmune. There is no blue graph coming up in the T-cell activation. There's no antibody production. Six weeks later, when we transplant unmodified iPSCs in gray, you see the bars coming up, and you see T-cell activation antibody production, high gray bars. That shows you that the hypoimmune transplants we did are not modifying the recipient's immune system. The NHP are capable of mounting a normal allogeneic immune response, so there is no immunosuppression after our cell transplant. We moved on into a differentiated cell type. I want to show you here our data also in the NHP model with primary islet cells, where we used primary islets, created the hypoimmune edits, transplanted those islets into the muscle location of an monkey without immunosuppression. You see the picture here is the follow-up 10 months later. Those islets are capable of surviving up to 10 months in this NHP without any immune rejection. When you compare to the wild type results on the bottom, you see that the islets are rejected quite fast, within 1 week. Another differentiated cell type we did was the T cells for our SC291, the hypoimmune CD19 CAR T program. We used here humanized mice. The immune system of the mice got humanized and is capable of mounting a human immune response. We then induced the CD19 positive NALM-6 tumor, and what you see after one month is that the tumor here is everywhere in those mice. When we are dosing with unmodified CAR Ts in the middle column or with SC291, that's our hypoimmune CD19 CAR, you see that the tumor gets cleared. Most of the CAR T studies stop there, and what we learn at that time point is that the hypoimmune edits don't seem to impact the function of the CAR T-cells. If we look a little bit later, what we see is because the mice, they do have a humanized immune system, they're rejecting the unmodified CD19 CARs, and you see here how the tumor reoccurs in those mice. On the right side, in the right column, you see hypoimmune. They don't get rejected, the tumor is under control. We performed that study for quite a long time, and after, like, 2 and a half months I just looked at the data. The tumor was still cleared in hypoimmune, I picked up the phone and called Terry Fry, who will present after me, and said, "Terry, how long do you want us to look at the mice? When will you be convinced that hypoimmune persists and is surviving in those mice?" Terry gave the great advice, "Why don't you just re-challenge the mice with tumor and see what happens?" That's what we did at day 83. We re-challenged the mice with tumor, and within only 4 days, you see how the hypoimmune cells cleared the tumor. That shows you that the cells survived, persisted, and they were functional after 3 months. This is one of my favorite slides. What it shows you is we could find those CD19 positive cells in the bone marrow and in the spleen of the humanized mice. When we looked at day 95, 3 months after the injection, what we found is when we gate around the CD19 positive population, that the phenotype, all surviving cells had the hypoimmune phenotype. MHC knockout CD47 overexpression, showing that there is an in vivo enrichment in the hypoimmune phenotype. Those are the CD19 CAR T-cells that survived and cleared the tumor after 3 months. Another model we did is the iPSC-derived islet cells. Here, the iPSCs were either unmodified or they had the hypoimmune edits. Those are human iPSC-derived islets, and we transplanted them into humanized mice. As expected, under wild type, when you look at the column here, the wild type cells, they do get rejected by the humanized immune system. Hypoimmune does survive. The follow-up here is 1 month. To get a functional readout, we induced diabetes into those mice. We used STC, and at the day of the transplant, what is here labeled with day 0, you see that the glucose levels are high. In the wild type group, where the cells are killed, the glucose stays high. When you look here on the right side, the hypoimmune islets, they are surviving, and they are functional. You see that the glucose levels over time are dropping, and the C-peptide was above the 500 picomole per liter target. After overcoming this allogeneic barrier in the preclinical models I showed you, we were really interested in the question, could we also overcome the autoimmune barrier in type 1 diabetes? We used a very common type 1 diabetic autoimmune model, the NOD/ShiLtJ mice. What we did in that model is we used NOD islets and transplanted them into autoimmune NOD mice. This is the same strain. The cells shouldn't get rejected. It's like an autologous transplantation in a patient. What you see on the left side is that the cells still get killed because of the autoimmune disease of the mice, of the recipient. You see there is no survival. The glucose levels, we induced diabetes here again, they stayed up. On the right side, you see when we introduced the hypoimmune edits into those islets, the cells are surviving, and the glucose levels are dropping, showing that those hypoimmune edits can also overcome that autoimmune barrier in that mouse model. We really wanted to study that in vivo with human cells as well. For that, we need an allogenic transplantation. We need the transplantation of islets into a mouse with the same immune system. The study design here was that we used type 1 diabetic patient PBMCs, and we generated mice, humanized mice. The mice have now the immune system of the type one diabetic patient. At the same time, we used the PBMCs, and we reprogrammed them to induce pluripotent stem cells, iPSCs. A bucket of them were left unmodified, wild type, and the other half we created the hypoimmune edits, the MM HLA class 1, class 2 knockout CD47 overexpression. The cells were differentiated into islet cells, transplanted into the very same mice. Now we transplant the islets into the mice with the same immune system, so there shouldn't be any rejection. What you see is when we do that with the wild type, that in the pictures, none of the cells are surviving because of the autoimmune disease in the type 1 diabetic patient we used. The cells are all getting killed. The mice, we induced diabetes. Again, you see there is no glucose control. The glucose levels stayed up very high. When we did the very same experiment, but we created the hypoimmune, we transplanted the hypoimmune islets, you see that the islets here are all surviving in the images. You see also here the graph, the BLI graph, and the C-peptide was above the 600 picomole per liter, and the glucose dropped over time in that model, showing you that in that humanized autoimmune model also we can overcome the autoimmune barrier. This is a slide Steve already shared with you, but I wanted to give you some details. This is the non-human primate. The study is still ongoing, where we induced diabetes, and what you see here, that the glucose levels in the beginning get really high. For two months, that NHP was controlled by giving insulin. We did the cell transplant. We taper down the insulin, and he's now since 20 days without insulin. That NHP was not immunosuppressed. If you look at the C-peptide levels, before we gave the STC, so before we made him diabetic, he was in the normal range. 50 days later, and on the day of the cell transplantation itself, the C-peptide is down. Seven days after cell transplantation of hypoimmune, and 14 days later, you see the C-peptide levels. We don't have longer follow-ups yet, but we are still working on it. As Steve already mentioned, we transplanted different hypoimmune cells into different NHPs. I think it was a totality of more than 40 NHPs we did. I showed you the primary islets, the iPSCs, but we also did iPSC-derived RPE, so cardiomyocytes. All the high-level summary was that all of those cells were able to survive and immune evade. There was no immune recognition by the adaptive or innate immune system. With that, I conclude that the Hypoimmune Platform does have the potential to overcome the transplant rejection barrier with no immunosuppression through the concept of immune evasion. As I showed you, we did so many different preclinical models that I was really running out of ideas what else to design to further study it. It is really time for us to move into the humans, and I'm very excited for the two clinical studies coming up later this year to prove the Hypoimmune Platform. With that, I hand over to Terry Fry, who will show you how to translate the hypoimmune platform into medicines. Thank you. All right. Thank you, Sonja. I'm going to walk you through where we're at with the allogeneic CAR T-cell platform. I think it certainly is not necessary to, you know, tell this from about the success that has been seen with autologous CAR T-cells. I think, you know, with the emerging, you know, real-world experience, it's pretty clear that CAR T-cells have consistently outperformed current standards of care. What we're seeing is that CAR T-cells are being moved earlier up in therapy, and we're seeing an expansion of indications. There's no doubt that we've seen challenges, you know, among them, you know, scalability, that is the ability to get these products into patients. The other important component that Steve didn't mention is the second bullet under challenges. I'm a pediatric oncologist, and I've been in the unfortunate situation of trying to manage patients during the 4 to 5 weeks between when they get apheresis and when a CAR T-cell is delivered. You know, during that time, you have a patient with progressive cancer, you have to administer chemotherapy, other agents that cause toxicity, and some of those patients actually don't actually get to the infusion. The last issue that I've spent a lot of time studying is that in spite of this success, it's certainly less than half of patients that will ultimately enjoy durable remissions after CAR T-cell infusion. You know, no doubt the allogeneic CAR T-cell, you know, offers the opportunity to address the issues related to supply chain and time to treatment since these products are available immediately for patients. As Steve mentioned, I think one of the biggest challenges is that we're not seeing the durability of remissions that we see, you know, with autologous CAR T-cells. You know, I'm personally very excited to get the hypoimmune platform that Sonja just described into an allogeneic T-cell and into patients, you know, to see whether we can address these challenges. Steve walked you through the manufacturing and the team has spent a lot of time, you know, optimizing, you know, this the manufacturing platform to enable consistent generation of high-quality CAR T-cells. And I'll just walk you through this briefly. You know, we begin with PBMCs, apheresis products from healthy donors, which are then T-cell selected. Using a novel nuclease Cas12b, three genes are disrupted, class one, class two, and the T-cell receptor to prevent the induction of graft-versus-host disease. We use lentiviral vectors to introduce both CD47 and the CAR gene. These cells are expanded and then, you know, aliquoted and vialed for delivery to patients. What the team has been able to achieve is a process that consistently results in high-efficiency gene editing, with 85% of cells approximately with full knockout of class one and class two. Following a selection step, 99.5% or greater of the cells being deficient in the T-cell receptor, which is important for the prevention of graft-versus-host disease. When we look across numerous manufacturing runs, and we sort of estimate the number of doses that we think we can generate, you know, per manufacturing run. What's that? Hello? On the webcast, can you guys put the slides back on? Keep going. Well, the screen went dead here. Hmm? All right. I think where I was at was saying that with the manufacturing runs, we estimate that per batch, that, you know, based on, you know, what we expect a therapeutically active dose to be, you know, from autologous cells, we're looking at about 450-500 doses in an oncology patient. Based on, you know, the emerging data in autoimmune diseases where the biologically active dose seems to be a bit lower, we're looking at over 900 doses per manufacturing run. Certainly, you know, a scale where we, as Steve said, expect that we can dose many, many patients with just a few manufacturing runs. Since we're editing the genome three times, I mean, one of the really important elements of the program has been to, you know, look deeply at the genomic integrity of the products, you know, that undergo the manufacturing process. We've done that by looking at a number of different types of analyses. The first is looking at editing specificity, and this was done using two orthogonal approaches. The second is to look at chromosome structural analysis using three orthogonal approaches, and then finally, you know, a set of functional studies to look for acquisition of oncogenic properties. I'm not gonna walk you through all the data that ultimately went into the IND, but this is just a piece of that data, just as an example, looking at the specificity of the editing. You know, and this is just showing, you know, analysis of 284 candidate sites. Out of, you know, analysis of a number of donors, only six, you know, loci showed up. Only two of those were recurrent, and when the team dug deeper at those, you know, both of those turned out to be, you know, due to artifacts. The bottom line is, I mean, this nuclease, this is a Cas12b, this is a novel nuclease, looks to be very specific in the context of T-cell manufacturing. The other important thing to figure out is whether or not, you know, the edits that we're introducing, in particular CD47, which was a novel introduction into T-cells, impacted the functionality of the T-cell product that was generated. This is a figure that was taken directly from the recent publication that Sonja mentioned earlier, looking at a comparison of the activity of hypoimmune CAR T-cells relative to, call it, standard CAR T-cells, allogeneic CAR T-cells in this experiment. Across numerous donors and in a couple of different tumor models, there was no evidence of impact on T-cell function. In fact, one of the things that we noted early on that, in most of these experiments, if anything, the hypoimmune CAR T-cells seemed to outperform, you know, the quote, "standard CAR T-cells." Last week, Crystal Mackall presented some data at ASGCT that potentially points to the mechanism here. What she showed was that when you knock out CD47 in a CAR T-cell and put them into NSG animals, the activity of the CAR T-cells markedly diminished, and they've attributed this to eradication or depletion of CAR T-cells by murine myeloid cells that are present in the NSG animals and are capable of cross-reacting with CD47 on the surface of the T-cell. It suggests that even beyond the allogeneic immune rejection component of the hypoimmune product, there actually may be a benefit in terms of potency with the overexpression of CD47. As Steve mentioned, the trial, called the ARDENT trial, is open and enrolling. It's a, you know, it's a fairly standard, you know, safety trial with a phase Ia component, a dose escalation. The starting dose is a dose where we would potentially expect to see some biologic activity based on experience with autologous CAR T-cell products. You know, the disease indications are shown there. I'll note that we're including CLL in the phase Ia portion. The other important point is we're using standard lymphodepletion. There's no enhanced lymph depletion with the goal of really understanding the ability for this hypoimmune platform to induce cell persistence. Once we complete the phase Ia dose escalation, we'll then embark on a series of phase Ib expansions in a number of different disease indications. Sonia already walked you through this experiment, and, you know, she pointed out the fact that one of the things that emerged from this was the ability to demonstrate enrichment of the hypoimmune cells in the humanized animal model, you know, due to protection from allogeneic immune rejection. As Steve mentioned, we expect that we'll be able to look at those same features in recipients, in human recipients of SC291. You know, the expectation, as Steve mentioned, would be that with recovery of the immune system, particularly NK cells which come up quite early, I'll show you that in the next slide, and T-cells, that there'd be depletion of the non-hypoimmune fraction with persistence of the, of the hypoimmune component. I think we'll be able to see that certainly, you know, out at 2-3 months, but even potentially by one month, we would expect that we would see some degree of enrichment. The reason I think we'll see that earlier is because, you know, we've known this for a long time in the transplant field, and this is also true for CAR T-cells. The first cell that comes back after lymphodepletion are NK cells. In fact, they come back quite quickly, and they often rebound to levels that are higher than what you see prior to lymphodepletion. When you wipe out class one, class two, these cells become literally sitting ducks for NK cell immune rejection, as Sonja walked you through. The expectation would be that CAR T-cells that aren't protected from innate immunity would be rejected quite rapidly in the first month. You know, with this immunoevasive property then, you know, our goal is to infuse a CAR T-cell that avoids early allogeneic immune rejection resulting in cell persistence, at least comparable to what we see with autologous CAR T-cells, with the goal of sustaining remissions in patients that achieve them. I'll just walk you back a little bit. I, again, I said I'm a pediatric oncologist. The first FDA approval for CAR T-cells was actually in pediatric oncology with Kymriah in 2017, and I was involved in some of those early trials in the early work at the NCI. You know, the CR, the remission induction rate in kids with leukemia was pretty remarkable. It was about 90% of patients achieved remission. Unfortunately, if you look at the data from the ELIANA trial, this was the trial that led to the licensure of Kymriah, you know, 50% of the patients achieving remission ultimately relapsed within the first year. The reason for the relapse really fell into two different buckets. You know, one pattern is the leukemic resistance, that is loss of the CD19 antigen that's being targeted by the CAR. Obviously not a problem with the CAR T cells, that's the leukemia intrinsic effect. The other pattern that we saw was that with early B cell recovery within the first 3 months after CAR T cell infusion, as evidence of lack of a functional CAR T cell persistence, the vast majority of those patients ultimately relapsed with leukemia that retained expression of the CD19 protein on the surface, again, indicating the problem with lack of cell persistence. I think it took a little bit longer for the lymphoma field to identify that same pattern. If you look at this early data from Cam Turtle from the Fred Hutchinson Cancer Research Center, this was a trial in which they looked at a couple of different lymphodepletion regimens. What they observed was that a subset of patients, you know, had durable persistence of CAR T-cells. Other patients, those not getting fludarabine, actually had rapid, you know, clearance of the CAR T-cells. If you look on the right-hand side of this slide, you know, what they were able to demonstrate was that with persistence of CARs, the durability of the remission went up in the patients that were treated in this trial. Steve already showed you this. This is data from the ZUMA-1 trial. I'll point out that this is actually a CAR with a CD28 costimulatory domain. Many people think that this CAR doesn't persist. In fact, if you look carefully in the bone marrow, you actually can find CAR gene in patients, you know, for long periods of time. In fact, if you look at this data in patients who achieve remission, you can find gene mark cells in 95% of them, you know, at early time points and over 50% even at late time points. You know, we really do believe, and I think the field has shown us that persistence matters, certainly, in leukemia. I hope I've convinced you that that's also true in lymphoma. It also is emerging as an important feature of myeloma. I'll talk about that in a little bit. You know, we believe that, you know, with immunoevasion, that if we can get, you know, CAR T-cells to persist up to two to three months, that would certainly would be, you know, longer than what we're seeing with current allogeneic CAR T-cell approaches. We actually think that, you know, we have the potential to see persistence, you know, longer than that in these patients. As Steve mentioned, I mean, the manufacturing platform in many ways is modular. You know, the gene editing, the cell modifications, you know, that we're doing can certainly be applied to other therapeutics, you know, and simply by swapping out the CAR itself, you know, we can then generate, you know, CAR T-cell products targeting multiple antigens. The next two programs after the CD19 program will be a program targeting CD22 in CAR refractory patients and then a follow-on program with a BCMA CAR. Importantly in both of those cases, we've in-licensed fully clinically validated CAR constructs. I certainly learned across a lot of CAR development work in my lab and taking a number of those in the clinic, that it's good to have human data to confirm activity. We also look forward to expanding into other targets in the future. You know, one of the things that, you know, we're certainly recognizing is, and I mentioned this briefly in my comments about leukemia, is that, you know, across multiple diseases, leukemia, lymphoma, et cetera, it's really less than about half of the patients who receive CAR T cells that ultimately achieve durable remission. You know, with an increase in the use of CD19 CAR T cells, we would expect that this CAR failure population will grow. Not a big surprise in the right-hand side of this slide are the patients who actually for whom CAR T cells fail, the overall survival is quite poor. You know, and, you know, this is certainly an unmet need. When I was at the NCI, you know, kind of before we even recognized this issue with relapses post-CAR, in about 2015, you know, we submitted an IND and embarked on a trial with a CAR targeting a different B-cell associated antigen, CD22. As we opened the trial, you know, we increasingly saw patients that were coming off CD19 CAR T-cell therapy. We published the initial paper, you know, shown in the middle there in 2018 in Nature Medicine. What we demonstrated was that we were able to induce remissions in over half of the patients, the vast majority of those patients who had received prior CD19 CAR therapy. You know, this CAR construct, it was taken into clinical trials in lymphoma at Stanford, demonstrating comparable remission induction rates in a lymphoma population. In the far left there, in recent data published at the DAW Oncology Conference, you know, in the updated data looking at all CAR failures, you know, they're looking at about a 50% six-month CR in these, in this patient population. Certainly a CAR that is quite active in CD19 CAR failures. You know, what we look forward to doing then is obviously expanding, you know, the allogeneic CAR T-cell platform to CD22 with the program that we call 262. This is just some data just demonstrating that, you know, we can incorporate this CD22 CAR into the Hypoimmune platform and demonstrate activity. The model is a little different than the models that we've shown previously. It's a Nalm6 tumor model, instead of injecting entirely a single population of tumor, we inject a mixed population with one component of that population lacking the CD19 antigen. When we treat mice engrafted with this particular mixed population with CD19 CARs, as you expect, you get some early activity, you get clearance to the CD19 positive fraction, then you get outgrowth of the CD19 negative fraction. If instead you inject a CAR T-cell targeting CD22 that is uniformly expressed across all of the NALM-6 tumor cells that are engrafted in these animals, you get complete clearance, you know, of these tumors. The second or the third place we'll take the Hypoimmune platform is into multiple myeloma. Certainly as Steve mentioned, I mean, this is a huge unmet need with a large addressable market and a large number of patients that aren't able to receive CAR T-cells due to access problems. As I mentioned, the emerging data in myeloma is corroborating what we're seeing in lymphoma, which is that some degree of cellular persistence certainly matters in terms of durability of remission in these patients. As you all are aware, there are 2 commercially available CARs, and one of the things that we're noting is that different than CD19, the quality of the binder seems to make a difference in the sense that we're seeing differences in outcome depending on the commercial CAR product that's being used to treat patients. As I mentioned earlier, we think it's very important to utilize a binder that has been validated in humans. The construct that we've in-licensed came from Miyaso. You know, CARs using this binder have been infused into over 100 patients with data presented at the last 2 ASH annual meetings. This is, you know, that data shown on the left-hand side of this slide, looking at overall response rates that are very comparable to the best-in-class BCMA CAR that is currently available. The other thing I'll point out is that when you look carefully using minimal residual disease or MRD monitoring in the bone marrow, one of the things that's very important is looking at complete eradication of tumor cells in these patients after CAR infusions at early time points. In addition to the response rate data shown in the graph, it's important to note that these patients actually achieved, you know, 95% MRD negative remission induction. Again, we've taken this particular CAR construct, incorporated it into the Hypoimmune platform, tested it across multiple tumor models. I'm only showing one here. Compared it to, you know, best in class, commercially available control CAR construct, across multiple donors have seen very comparable efficacy in multiple tumor models. You know, just in summary then, you know, we think we're well positioned to deliver, you know, CAR T-cell solutions for multiple, you know, populations of cancer patients. We've got a platform, and manufacturing capabilities that, you know, that can generate, you know, large numbers of high-quality products from single manufacturing runs. We're incorporating clinically validated, you know, CAR constructs, both CD19, CD22, and then BCMA, with an emerging pipeline of next generation targets that we're currently, you know, working on, you know, with the goal of really generating off-the-shelf medicines, you know, at manufacturing scales that will address, you know, a huge unmet need. In terms of upcoming milestones, as I mentioned, the IND for 291 is cleared. The trial's open and enrolling. It's received a Fast Track designation from the FDA. Really at this point, we're just looking forward to early clinical data coming out this year, which we think will really give us a lot of information about the Hypoimmune platform for the first time in humans. Looking forward to submitting an IND by the end of this year with SC262, the CD22 CAR for CAR refractory patients, and then the BCMA CAR expected in 2024. With that, I'm gonna turn it over to Doug, who's gonna walk you through the autoimmune program. Good morning, everyone. Very nice to be here, and very nice to be a part of Sana. I'm now in my second month in the company, and I have to say that, as you're seeing this morning, the quality of the science that's being done at Sana, is really pretty exceptional. The people as well, who really are moving that science along, including the folks back in the labs, many of whom I think are probably listening to the webcast, and I'm happy to be presenting their data, as part of the presentation here today. I'm gonna talk about autoimmune and inflammatory diseases. I may lapse into the jargon of ANI, so that's what I mean if I happen to say that. I've been involved in this area for a very long time. Steve said 2 decades. It's actually 3. I don't wanna date myself. I do look back to really what I think is the first renaissance in the treatment of these types of disorders, which was the launch of the cytokine inhibitors back in the late 90s, followed in really the same vintage as the B-cell depleters, Rituxan being the first of a whole line of molecules that were very efficient at depleting B-cells and have now moved into being mainstays of treating these variety of different autoimmune diseases. Just to reorient you again to the construct that we'll be taking forward here, SC291, this is a HIP allogeneic CAR T-cell. It has all of the edits and the knock-in of CD47 and the CD19 CAR. You heard Terry describe that in the context of the oncology studies we'll be carrying out. The opportunity here is really enormous. This is a collection of more than 75 distinct diseases. Some you've heard of, some you've probably never heard of. But many of them have an underlying B-cell pathology. I think that's been proven very clearly over the last 25 years. lupus nephritis is one example. It's particularly pertinent in light of a paper that was published at the end of last year. It's a large opportunity with more than 100,000 patients in the U.S. who suffer from this disorder. One of the great things about SC291 is that drug's available right now. We actually have material that's been manufactured, which could move very quickly and allows for us to move very rapidly into this disease indication or disease indications, shall I say. The evidence for B-cell depletion in autoimmune diseases, as I said, goes back 25 years to the launch of Rituxan, really. I think that's where the story starts in a very clear way. If you think about what's happened over the years, first there was Rituxan, then there was Ocrelizumab, and now there's Obinutuzumab. Each of these drugs, each of these antibodies, is a little bit better at depleting B-cells, and the efficacy has improved along with the depth of B-cell depletion. There's really no better way to deplete B-cells than a CAR T. If you want depth of depletion, a CAR T that targets CD19 is really the way to go to really maximize the depletion. You can see on the right-hand side of the slide some of the diseases where B-cell depletion has already shown itself to be an important treatment paradigm. A large number of diseases, and these are all lifelong diseases. There's an accumulation of damage in these patients that occurs over a lifetime of not only the disease itself, but the treatments that we impose on them. There's a huge opportunity here for B-cell targeting. We know that B-cell targeting is effective, so there's a roadmap sitting right in front of us in terms of where to go, what to do, and the diseases to focus on. The, I guess, paper that got everyone buzzing in the field is really this paper from Nature Medicine that came out at the end of last year, Autologous CD19 CAR T-cell therapy in a population of very severe lupus nephritis patients. You can see the SLEDAI scores for the 5 patients who were enrolled in this study. All of them have very active disease on a collection of meds that really were unable to control their disease. 3 months after the CAR T treatment, complete resolution of their SLEDAI scores. Remission is induced very quickly in this population of patients. It's quite remarkable the speed of onset of this type of major clinical effect in these patients. What was also quite striking is if you look at all the various biomarkers that have been used routinely, proteinuria, anti-double stranded DNA antibodies, fatigue, which is really kind of a crushing quality of life issue for these patients, all of them resolved almost completely within a few months. I think the encouraging side of the data as well is just how well tolerated the therapy was in this population of patients with only a little bit of CRS, fever in 3 of the 5 patients for 2 days duration. So very benign from a safety perspective. No ICANS in these, 5 individuals. They're off all drug therapy now. 3 months after the induction, if you will, with the infusion of the CAR T, these patients are completely off any other drugs. Are in complete remission in terms of both the SLEDAI scores as well as all of the biomarkers. Quite remarkable how these have all normalized. We're now 18 plus months of drug-free remission in these patients with the last follow-up that was reported at one of the recent medical meetings. What's fascinating here from an immunology perspective is that the recovery of B cells occurs about 100 days out, pretty uniformly across all of these patients. The recovery of these B cells, these are naive B cells. They don't induce flares. They don't induce disease. It's almost that these patients have had a complete immune reset as a result of the CAR T therapy. Quite an exciting set of observations. A more recent publication that came out on an individual case report in antisynthetase syndrome, again, with an autologous CD19 CAR T. You can see the decline in the diagnostic autoantibody that's associated with this disease within six months back below baseline. The inflammatory consequences of this disease you can see on the MRI with complete resolution again in three months. Two diseases, two very quick remissions, and these are remissions in these patients. It's not clear yet how durable these are, but certainly with the 18 months and counting in the lupus nephritis patients, it's quite encouraging that these will be long-term durable remissions in these patients. Our plan is obviously to utilize the existing SC291 drug supply. We think there's an opportunity, and we've seen others who have announced this, to focus on sort of a basket study, that is obviously to include lupus nephritis patients, but to really pick and choose amongst that laundry list of B-cell responsive autoimmune diseases, the roadmap as I described it, and to pick diseases where we think there's the greatest likelihood of success as part of that basket. The HIP technology, we hope the persistence and the ability to evade both adaptive and innate immune responses, we think may give us the opportunity to explore lower lymphodepletion. If that's true, it really opens the door to a much wider cross-section of patients, if we can dial down that lymphodepletion dose, as part of the preparative regimen for the infusion of the CAR T. Again, we think we're uniquely positioned from a manufacturing perspective to really be able to address what is a very large market and to be able to go out and produce materials to treat tens to hundreds of thousands of patients given the manufacturing technology investments that have been made already. Really an exciting opportunity. We're clearly not going from a standing start on this program given that we've already filed the IND for SC291. Moving into autoimmune inflammatory diseases is obviously something that we're quite excited about, and we'll have more to say about the specifics and the timing of the program as we get closer. Suffice to say, we see this as an enormous opportunity for the platform. Again, looking forward, if we focus only on the CAR T portfolio, I think Terry alluded to this already in his talk, there's a number of validated targets. To some degree, all we need to do is to swap out the binding domain in these CAR constructs, we can iterate quite quickly through CD19, CD22, BCMA, and others. That's the near-term opportunity in hematologic malignancies. Complemented, as I just said, by the opportunity in the autoimmune diseases, which is in its own right an enormous standalone opportunity. As we look further out into the future, new targets, solid tumors, we think that this is sort of the gift that keeps on giving, the investment we've made in the manufacturing technology will serve us well to be able to address all of these various markets as we go forward. I'm going to switch gears now, and talk about a completely different topic and to some degree a separate platform that's being developed at Sana. This is the islet cell program, SC451, for the treatment of type 1 diabetes. Excuse me. I'm sure all of you are familiar with type 1 diabetes. It's a very large unmet medical need. It's a disease where we know the causation and that's an autoimmune destruction of the beta cells in the pancreas, which results in an inability to control blood glucose levels. About 4 million people, just north of 4 million people in the U.S. and E.U., there are no curative therapies. We can manage these patients to some degree, but certainly cures have been elusive for this population of patients. That said, there's been an enormous amount of progress that's been made over the last, I guess, 100 years since the discovery of insulin, and that includes, you know, some of the tried and true things like dietary restrictions to manage the disease, but also innovation around diabetes or, excuse me, insulin administration with pumps and real-time monitoring of glucose levels in patients. A lot of progress, a lot of improvement in the standard of care, but this is a disease that's characterized by a number of long-term complications because patients can't perfectly manage their diabetes, and that results in stroke, heart attack, a variety of different consequences that develop later in life. That's particularly true for folks that are diagnosed in the first 2 decades of life. There's a shortened lifespan in those individuals. The graph on the right is some recently published data which really highlights the fact that the ability to achieve this target Hemoglobin A1c level is really difficult to do, and we're looking at two different timeframes here. What's odd to see is actually things have gotten worse, particularly in patients who are sort of in their adolescent years, between 10-20. You see that blue curve showing the spike in the Hemoglobin A1c levels. You know, for reasons that are unclear, patients seem to be worse off in terms of managing their disease, even though all of these new innovations have come online. I think the path forward has really been identified here with the ability to transplant islet cells. That's really the ultimate solution to the problem. The current standard using allogeneic islet cells suffer from the fact that there's limited availability of the islets to begin with, only a handful of patients really have the opportunity for this. It's also a situation where these patients are subject to lifelong immunosuppression. As Sonja mentioned already, that comes with its own set of consequences. It's promising in that for some of the phase III data that's been reported, roughly half the patients can achieve insulin independence. Obviously the challenge for them is to stay on the immunosuppressive therapy. If they come off, they obviously reject the graft and lose the ability to get the benefits of this transplantation. This is the path forward, allogeneic islet cell transplantation, ideally in the absence of immunosuppression. We sort of see the problem, I think, in sort of three major categories. In order for allogeneic islet cell transplantation to become the norm, there's three barriers we've got to overcome. The first on the far left, I think Sonya very elegantly highlighted those. There's allogeneic transplant rejection, so the immediate rejection of the allogeneic cells. As well, there's the autoimmune rejection of the beta cells, the immune assault and deletion of the beta cells in the pancreas. We have to be able to scale, right? In order for this to be a broadly applicable technology, we need to be able to treat the nearly 4 million patients or more than 4 million patients in the EU and US. Finally, there are improvements that could be made and probably should be made in the way in which the islets are transplanted, so the location of transplantation and trying to move away from this portal transplantation procedure which has its own set of issues and limitations. Our solution, SC451, is an islet cell population that is allogeneic. It's derived from iPSCs. It has all the hypoimmune edits, and we think this solves many of the problems that are incumbent on the allogeneic islet cell transplantation field. You've already seen that, as far as solving the immune problems of allogeneic transplantation, that both allogeneic and autoimmune rejection, the preclinical data that Sonja shared with you earlier shows that we may have solved that problem, and certainly the preclinical data suggests that that's the case. Problem number one appears to be under control with the hypoimmune edits. The second problem, which is scale, the ability to treat enough patients to really make an impact, we're focused on iPSC-derived islet cells. The process here involves creating a master cell bank, sort of a tried and true technology in biologics drug manufacturing. In this case, what we'll do and have done is to actually edit those iPSCs to knock out HLA class one and two and to knock in CD47 expression, the as Sonja described, the HIP modifications that we do routinely. Those cells can then be differentiated into islet cells and can form the basis of the transplant itself. This is the method that we've developed to create these hypoimmune glucose-responsive islets that can then be transplanted. The third leg of the stool here is implanting these in the intramuscular site that I'll talk about in some of the slides that are coming up. We think this offers a lot of advantages for patients and really represents a step forward in terms of the implantation site and how simple that would be in comparison to portal administration. I won't go through this data in any detail because you've seen it already. Our slide with the primate pops up again. It's an important slide here. It is more evidence that we're able to overcome the allogeneic rejection. We've seen that in mouse models. We've seen it in non-human primates. We're now moving to the stage where we're hoping to see that in humans before too long. Suffice to say that there's an overwhelming body of data showing that we can overcome the allogeneic rejection in these preclinical models. The same is true when it comes to the autoimmune rejection, so the other form of rejection that's important to overcome in that first sort of barrier that I described in one of the previous slides. Again, I won't go through the specific data except to say that this very elegant mouse model that has been developed by Sonja and her team really highlights the fact that you can transplant these HIP-edited islet cells and see glucose control and see them circumvent the various forms of immune-mediated rejection, both autoimmune and allogeneic. The second major barrier, scalability. Again, the approach that we're taking is to create an off-the-shelf platform that allows us to make large quantities of islets that we can transplant into patients. We have an iPSC line. Actually, we have several lines. These have all of the appropriate donor characteristics. They're compliant with 21 CFR. They have pluripotency and genome integrity. All of this is being very carefully monitored. We're creating GMP hypoimmune master cell banks. These are the cell banks that allow us to basically carry out the necessary edits to create the hypoimmune modifications in those cells. We have a safe harbor site that's been very carefully selected to maintain the phenotype of these cells. Finally, we are able to actually differentiate these iPSCs into islets and islet clusters that then form the basis after cryopreservation of the materials that will be transplanted into patients. This is a very rigorous process. There's a lot of analysis that goes on behind the scenes here to look at both the genome stability of these lines as well as the phenotypic characteristics of the cells that actually represent the drug substance. Just a little bit of data from some of the laboratory studies, some of the early studies showing that when we differentiate these iPSCs, we can generate populations that have a high degree of beta cell purity, which is obviously what we're shooting for, a higher degree of endocrine purity, so a mix of the various different endocrine cell types that you typically find in the pancreas. They cluster into these islet-like clusters. In vitro they produce insulin in response to glucose stimulation. Phenotypically, we're able to derive cells that meet the criteria we're looking for for transplant purposes. Again, when you do transplant them, they do work. This is some data that Sonja showed a few moments ago in this model where we're able to actually transplant the cells, see the C-peptide levels increase, and you can see in the far right-hand panel there, the glucose control labeled panel, that we are able to control glucose levels in these animals post-transplantation. Proof of principle, proof of concept that when transplanted, we can reverse the Type I diabetic process in these animals. Safety, always something that you think about with respect to, deriving cells from iPSCs. We've been very careful to build in sort of multiple layers, into this process. I think given the route with which we're going to use for transplanting these cells into the muscle in the forearm, certainly if there's any uncontrolled cell growth that's observed, the first step would be to simply remove the graft from the site of administration. There are other levels and other layers of protection built in as well. A safety switch that has been incorporated that allows us to give an approved agent and sort of dial down and kill off the proliferating cells over time, as well as because we have high levels of CD47 on these cells, we're able to administer an anti-CD47 antibody, and then very quickly you can see the removal of those cells following antibody administration. Really 3 levels, if you will, of thought around making sure that we have adequate safety measures in place for moving this program forward. Last but not least, the third barrier we think to really making this available on a wide scale is the intramuscular site for islet cell transplantation. As you know, many of the prior studies have used portal vein infusion as the method of administering. This is an invasive procedure, requires an interventional radiologist. There's some limitations associated with access there. There are issues related to bleeding and portal vein thrombosis that are not insignificant, certainly measurable consequences in this population of patients. There's a phenomenon known as IBMIR, and you can read the definition there of what that is. It's basically a process whereby complement activation causes sort of an immediate loss of up to half of the cells that are actually infused. Cell loss is a consequence of this process, and frankly, it's difficult to monitor the graft with this route of administration. We think the ideal approach to this is the intramuscular islet cell transplantation approach, we can deliver this more readily, certainly scalable for a larger population of patients which we hope to access. We think that it'll overcome this IBMIR phenomenon. We can monitor this, we can monitor the graft non-invasively. Very easy to assess the progress of the graft post-implantation. There is evidence clinically and certainly an abundance of evidence with the data in non-human primates that Sonja shared, that this approach to engraftment actually works. Onto the investigator-sponsored study that we plan to initiate here soon. It's a phase I study. It's being carried out by very experienced investigators in the islet cell transplantation field, so a lot of skill in the art. The process that we'll be following is actually pretty straightforward. I think Steve mentioned this at the outset, where we'll be harvesting donor cadaveric islets. We'll put them through their paces with the HIP modifications through the standard process, then transplant these into a Type 1 diabetic patient without immunosuppression. Important to highlight that this is without immunosuppression. Back to the slide you've seen a couple of times. In some ways, what we're doing with the IST is very analogous to what was done in this primate experiment that you've seen before. What you can see here is the cell transplantation dialing down the insulin levels. This animal is now insulin independent with roughly three weeks of follow-up here. C-peptide levels normalize. This is very much what we're hoping to see in the patients that will receive these edited islets. A little background work was done just to make sure that the editing process and the HIP modifications didn't have a negative impact on the composition of these islets as well as their ability to produce insulin. This was an experiment that's been done several times now. If you look at the middle panel there, the colored bars, you can see that the distribution of alpha, beta, and delta cells is equivalent across either edited or unedited cells that were just manipulated in the same way through the process. In both cases, on the far right, you see very robust insulin secretion in both the wild type as well as the HIP islet cells. Quality, if you will, is maintained even through the processing and the HIP modification. We're on track to actually initiate this study later this year. The goal of the study, very straightforward endpoints, is to look at cell survival and immune evasion, to look at C-peptide levels in these patients, and hopefully to see some enhanced glucose control. Again, this is against the backdrop of no immunosuppression. A lot of progress in this program and more work to be done, but we've demonstrated now the ability to deal with both the allogeneic and autoimmune rejection phenomenon. Demonstrated activity in relevant preclinical models. The manufacturing process is well underway in its development. Again, I mentioned already that the IST will start later this year, and we hope to have some preliminary data. Very exciting times for the diabetes program here, anticipating that SC451, the actual product candidate, will have an IND filed sometime in 2024. I'm gonna turn it over now to Steve Goldman. Steve, as was mentioned, is involved in glial progenitors. In my past life at Biogen, we had a lot of interest in the MS franchise in trying to come up with approaches to be able to remyelinate. We were trying to do that through pharmacologic approaches, antibodies, small molecules, going after oligodendrocyte precursor cells. I think what you'll see from Steve is light years ahead of that kind of work and really an opportunity to reverse some of the damage that's been done in a number of not only autoimmune diseases that affect the brain, but many other diseases of the brain that involve myelin as well. Steve, real pleasure. Thanks, folks. I'm a neurologist, and, you know, of course, I study brain disease. In my case, exclusively brain disease. But neurology by definition is study of neurons, right? And neurons, of course, are the primary conductive cell type of the brain, allowing impulses to go from one part of the brain to the next. That tells you something right there, that neurology is the study of neurons and brain disease. The assumption was always historically that brain diseases were from loss of neurons or dysfunction of neurons. What we've come to appreciate really in the last 10, 20 years is that really the majority perhaps of diseases of the nervous system are primarily diseases of the support cells in the brain, the glial cells. That's what the focus of the CNS group at Sana is, the study of the glial cells and replacing glial cells as a means of treating brain disease. Really by way of education, if you will, you know, for those of you who aren't familiar with the brain, basically neurons are the conductive cell type of the brain. There are two primary support cells in the brain. They are the oligodendrocytes and the astrocytes. The oligodendrocytes are the myelinating cell type that Doug just mentioned. Basically, they provide myelin, which is the insulating sheath around axons being neuronal fibers that allow impulses to be conducted from one neuron to the next. Astrocytes are the support cells of neurons that provide direct metabolic support and, also maintain the blood-brain barrier, basically allow fluid transport in the brain. These two cell types are both derived from a common progenitor. That's the glial progenitor cell. Glial progenitor cell is by potential. It persists in our brains, right? Together, these cells are actually more abundant than neurons. In the adult human, depends on what part of the brain you're talking about, but the majority of the cells are glial cells. Basically, we tend to run about a third astrocytes, about a third oligodendrocytes, about a third neurons across the brain overall. There's a substantial proportion, about 5% of the cells in our brains are persistent glial progenitors. What I'm gonna really discuss is the use of the glial progenitor cell as a therapeutic vector. The bottom line is, at this point, we know that the glial cells that derive from the glial progenitor really form the basis for most of the myelin diseases, many of the neurodegenerative diseases. We've learned how to make these cells, to produce them under GMP conditions at scale and purity, and have looked at them in a broad variety now of diseases where we see the potential to replace endogenous diseased glial progenitors and their derivatives with essentially fresh, healthy cells that then allow the production of new astrocytes and oligodendrocytes in the brain. That allows a really broad platform of and a broad set of diseases to be targeted with one common product. That's the theme of everything I'll show you now. So, you know, as I mentioned, the glial cells occupy most of the brain. The oligodendrocytes are primarily in the white matter of the brain, okay? The white matter underlies the cortex. The cortex is essentially comprised of neurons, but also of astrocytes. Astrocytes are also, though, in the gray matter. Astrocytes in the gray matter and the white matter, oligodendrocytes in the white matter, the astrocytes of the gray matter are supporting synapses, are supporting the connections between neurons. What happens as a result is if there's a neuronal disease that also involves glia, and we replace the glia, that can rescue the synapse and therefore rescue the neuron. That's another theme that we'll focus on. It's a broad set of diseases that are diseases of myelin. First and foremost are the pediatric leukodystrophies. These are storage diseases and hereditary diseases, congenital, where myelin doesn't form properly. These are relatively uncommon, but as a group, they're actually the most common set of neurologic diseases of children. Unfortunately, most of them are lethal with very few treatments available for any of these diseases on this list. In adults, of course, we think in terms of multiple sclerosis as a common neurologic disease. Progressive multiple sclerosis, which essentially is a phase where patients essentially develop a neurodegenerative disorder downstream of losing myelin because myelin and oligodendrocytes are required for neuronal viability as well. Even the white matter diseases of the elderly, diabetics, of hypertensives, all of these represent a loss of myelin that results in significant neurologic dysfunction. It's a broad category of disease. Over and above the myelin diseases, we have the neurodegenerative diseases, things like ALS, Huntington's disease, frontotemporal dementia, which we've always thought of as neuronal. In fact, there's so much synaptic dysfunction because of the astrocytic disorder in these conditions that if we replace astrocytes, we replace actually much of the synaptic function neuronal viability. It's a category of disease that we look at favorably in terms of using, again, this one common cell type of glial progenitor to treat. This was our first use of the glial progenitor, if you will. We isolated these cells initially from fetal tissue and long since have moved on to stem cell derivatives, which we'll get into. This is just a proof of principle where we've taken glial progenitors and transplanted them into neonatal mice. These are human cells, and it makes the point that these cells are extraordinarily migratory, right? It's a developmental phenotype where these cells are intended to be in a developing brain, and their job is to migrate through the brain, right, and set up shop. That's what they do if we put these cells into, in this case, a neonatal mouse. These are all human cells. Every red dot here is a human cell in a single 14-micrometer section. You get the idea that these cells really take over, and in fact, they do. In this case, we've gone into a hypomyelinated mouse. It's a hypomyelinated mutant called the shiverer mouse that doesn't make any myelin. No myelin in these animals we'll see die young, you know, very, very quickly, typically by about 20 weeks. We can rescue these animals by transplanting these cells in neonatally. In this case, we end up with these mice where all the cells, the donor cells, have migrated through. They've taken over. They've literally kicked out the deficient population, and then they go ahead and myelinate. This is all human myelin, which is interesting. Makes for an interesting disease model because we can look at the effect of basically different human-disease-derived cells in these models as well. That's a topic for another day. The bottom line is we can completely remyelinate these nervous systems, and these animals are rescued. This is an example of that. Nikki, if you could turn this first one on. Thank you. Here's what Shiver mice look like. This is at 18 weeks of age, about two weeks before they die, and they die like clockwork typically. And what happens is as these animals are growing older, they get larger, and as they get larger, axons get longer, and since those axons aren't myelinated, there's more and more conduction failure. First they become ataxic, imbalanced, lose trunk stability. Then they develop leg weakness, first the hind limbs then the forelimbs, then they start seizing, and then they die of status epilepticus, typically recurrent seizures. Next over here, this is after a transplant, and this is at 13 months we looked at this guy. He made it up to 2 years. He was fine. What's remarkable here is not just the rescue of the animals, but early on, these animals, the transplanted animals, develop a neurologic dysfunction. Takes a while for the grafts to take, they slowly but surely get better, all better, back to normal and rescued. We have every reason to think that that's what we'll see as we go to patients as well. We've looked at these cells in rat models and squirrel monkeys. We see the same type of effect. Because of that, we realized that, okay, these cells really have therapeutic potential, and the use of fetal tissue would never be really scalable in any reasonable fashion. Some years back, we developed the methods for making these cells from pluripotent stem cells, both from iPS cells and embryonic stem cells. Here we're looking at what these cells look like in this 7-step preparation protocol that we've developed that allows us to make really, you know, highly enriched populations of glial progenitors from embryonic stem cells or iPS cells. It's a process that takes a while. It's a several-month process. When we first published it was out to about 160 days. Now we have that down to about 120, but it's still a long process. That's one issue, but the flip side of that is by virtue of the long differentiation, it turns out that it's an extremely efficient population at the end of the day, and that almost all the cells are glial progenitors. Those that are not are fibrous astrocytes. There's nothing left in these preparations by way of undifferentiated cells. That gives us a lot of possibilities in terms of manipulating the cells at the iPS or ES stage, whether putting in hypoimmune edits, which are a little different in the brain than the systemic edits that Sonja's discussed. It's the same idea. We can put in hypoimmune edits. We can engineer for competitive advantage. There's safety switches that can be put in as well if needed. Basically, it's a cell population that we can edit up front for if needed, and it's not necessarily needed. In our first go-around, we'll be using really unedited cells. You'll see that that's more than sufficient in terms of both safety and efficacy. Of course, we are looking for, you know, for the potential for really manipulating these cells further for, in a disease-specific fashion down the road because there is such a long list of diseases that potentially this one product can treat. The cells really are remarkably safe, and it's because of that long differentiation process and the efficiency by which these cells become glial progenitors. These are single-cell RNA plots where we've looked at undifferentiated ES cells in this case, and then, the cells after they have been. This is a different cell population, of course, but a matched cell population after they have generated glial progenitors in vitro. You see the really complete lack of overlap of the gene expression patterns, right, in terms of the glial progenitor stage in vitro versus the cells from which they derived, right? Again, it's about a four-month derivation process. We went further, transplanted them, and then took the cells back out of the brains and then did the single-cell RNA sequencing of the human cells that were removed back out of those brains. There's essentially no overlap whatsoever of the integrated gene expression pattern in vitro versus in vivo because there's a lot of context-dependent differentiation further after these cells are transplanted, and certainly none in terms of overlap with the undifferentiated ES cells. Accordingly, we have looked at hundreds and hundreds, probably well over 1,000 animals with that have received grafts from this cell line, and have never seen anything malignant, anything by way of undifferentiated tumorigenesis. Whoops. This is what the cells look like when they come out in terms of basically the composition of the cells that are removed back out of these brains. The human cells again, basically extracted back out and then analyzed. Basically, all the cells are either astrocytes or oligodendrocytes or persistent glial progenitor cells. Those persistent glial progenitor cells provide advantage because they serve still as a reservoir for making new astrocytes and oligodendrocytes as needed. So everything I've shown you up to now, though, basically were comprised of grafts of human cells into mouse, right? The human cells are taking over the mouse. What happens if human goes into human? Of course, we wanna be able to mimic the clinical situation. What we find is that, and this is really, really quite remarkable. We in this case set up a chimeric brain with a human Huntington's disease mutant glia and then transplanted in nine months later, healthy cells. These healthy cells then outcompeted the mutant Huntington-expressing glial progenitors and literally replaced them over time, essentially kicking them out. That results in the human-on-human replacement, which tells us it's predictive that this should work every bit as much in people going human into human as, of course, in these experimental models. It's, you know, it's a well-published set of studies in terms of the use of these cells for treating the myelin disorders, but also in the astrocytic disorders of the neurodegenerative diseases, Huntington's, even, frontotemporal dementia, schizophrenia. In all these cases, we see the replacement of host cells by donor. That can basically, effectively replace that diseased cell population with new cells. The opportunity is to treat a broad set of diseases with one product, but we're focusing initially on just 3. They include Pelizaeus-Merzbacher disease, which is a relatively uncommon disease of children where it's the closest thing in clinical practice that we'll see to a shiver mouse, where basically the these poor kids don't make myelin. They make a very dysfunctional myelin, I should say. But we're looking to potentially replace the dysfunctional oligodendrocytes of these children with new oligos made from the glial progenitor. Secondary progressive MS as an adult target. In this case, we're both trying to put in new oligodendrocytes and also getting some degree of repair of lesions that have already occurred. Huntington's disease as largely an astrocytic disorder that also involves dysmyelination, where we think we can replace these populations, and effectively treat the neurodegenerative disorders as well. Just running through these really quickly, Pelizaeus-Merzbacher, we see this loss of myelin, okay? Here we're looking at another image of the brain, but it doesn't have the kind of white matter we saw earlier on, right? It's very, very thin white matter. This is what needs to be replaced in these kids. Here's patients with chronic progressive multiple sclerosis, and you can see normal brain, but then after the initial stages of relapsing remitting MS, we see some loss of myelin. What happens is in relapsing remitting MS, patients progress to a later stage of progressive multiple sclerosis, secondary progressive, which essentially transitions to a neurodegenerative disease, right? Because neurons are lost because oligodendrocytes aren't there to support them. This is the phase of secondary progression that we're trying to rescue. We're trying to prevent this ongoing loss of neurons due to the loss of oligodendrocytes, and at the same time, potentially to reverse the deficits of these patients. Then Huntington's disease as a really in this case, an astrocytic therapeutic target. By, again, rescuing the synapse by virtue of putting in functional astrocytes, we see the ability to rescue the neurons that are at those synapses as well. That's something, again, we've gone from a number of different disease models at this point that have validated that point. This is what a normal brain looks like at the same level as a Huntington's brain. It's a remarkable degree of atrophy that these brains undergo. First and foremost, there's loss of the striatum, which is the putamen and caudate. These are the basal ganglia of the brain, the motor control regions. It's really by injecting cells early on that we expect to rescue these brains. Basically, we're looking at, you know, a really encouraging set of studies at this point. Everything we've done in animal models has played out well. I'm sorry. At the same time, we have scaled manufacture of these cells, certainly enough to entertain a number of IND-enabling or in phase I studies at this point. We're undergoing the IND-enabling studies at this point. Our goal is certainly an IND, perhaps several INDs, based on the same product in 2024. This really cuts to the chase. You know, we are all undergoing age-related white matter loss. It's one of the major causes of adult dementias. You know, Alzheimer's gets more credit than is due in that setting because about half of all adult dementias come from loss of white matter. You know, aging itself is a disease when you get down to it. What we find is that young cells will outcompete old cells. Young glial progenitors put into an isogenic brain will outcompete older. We see the ability to potentially replace these cells in an ongoing fashion in a broad variety of diseases as well as in, ultimately in the setting of aging. I'll close with that. Next is Richard Mulligan. When I was a grad student at Rockefeller, this guy was one of my heroes. That's already, you know. You really were. That's a testament to. You are that much older than me. I never knew that. That's a testament really to the science at Sana. Well, that's. There we go. ... terrific introduction. Thank you. There you go. Okay. We're gonna now turn to something very, very different, equally interesting. As Steve indicated, we have from the get-go had both the HIP technology platform and importantly, the in vivo delivery platform. What I'm gonna do is just introduce you to the fuses of platform, really giving you the why is this interesting, and the how do we do this? Then the fun stuff comes after me, where Terry and Ed will tell you that this really works, and it really works very powerfully. The why is very straightforward. For someone like myself who's been doing this for a longer period of time... yeah, we don't need that anymore. Longer than, you know, before some of you guys were born, the evolution of gene therapy has always been to kind of the aspiration to treat more patients more effectively, more diseases. What we've seen is a natural progression of the two approaches to gene therapy, the ex vivo gene therapy and in vivo gene therapy. The ex vivo approach basically exemplified by removal of cells from the patient, transduction of them in vitro, and retransplantation of them. It's been very, very powerful. Terry has always already gone through the whole value of the technology for CAR T cells. You've also heard the value of the technology for treatment of diseases like beta thalassemia and sickle cell anemia. Terry's also showed you the next evolution of the ex vivo therapy to go away from autologous cells to allo cells, increasing the accessibility, the number of patients we can treat. Ex vivo technology has also always been looked upon as limited in its scope of application. Not only is there the need to manufacture the product in a way outside the body, but there's also just a logistical problem of getting enough cells to treat enough patients. In vivo technology has been very, very powerful as well, but we're now beginning to see some of the limitations. It's those limitations that have caused us to be very, very interested in the technology I'll talk about. In vivo gene therapy has been very successful, particularly using vectors like AAV and LNPs. AAV, very useful for treating a number of rare diseases for local delivery of blood clotting factors and so forth. LNP is very, very valuable for local delivery of vaccines, as you know, and also for the treatment of diseases of the liver because LNPs largely go to the liver. As the in vivo therapy field has evolved, you see the limitations, and the limitations are essentially that you really more than ever are getting the sense that we really need to direct in vivo gene therapy to the desired target cell. In the case of AAV, for instance, to try to treat a disease that's a disease like muscular dystrophy, we found that you really have to push the system. You have to push very large amounts of the gene delivery agent, what you see as a consequence is you're hitting cells other than the cells you wish to hit, in particular liver cells. If one can get a better AAV system, we'll have a better therapy, okay? In the case of LNPs, they're not exactly amenable to, at this point, to delivery of genes or payloads outside of the liver. People are working in both AAV and the LNPs to give this technology specificity, we're not there yet. There's a safety issue of not getting into the proper desired cell. From a regulatory point of view, I think people are becoming more and more concerned about the off-target effects, the problems with gene editing that are surfaces about lack of specificity and so forth. It's very, very important, all of us think, to be able to limit transduction, limit the payload delivery to the cells of interest. A second major limitation of existing in vivo approaches is when you get into non-desired cells, you can have immunological consequences. A clear understanding that if you introduce genes into, for instance, immunological antigen-presenting cells, you have the opportunity to mount an immune response against the gene and the vector itself. Those are a couple things. Lastly, and probably most important for a gene therapy guy like myself is the potency is very much affected by the inability to infect, transduce only the target cell of interest. That is to say, the body provides a sink for the delivery, and if you wanna get the virus in a certain location, you don't want it going to another location, like in the case of muscle, you don't want most of the virus to go to the liver and not to the muscle, the cells of interest. The system that we've developed takes off on this principle, and it's absolutely designed to address these issues, to get absolute cell-specific gene transfer in the desired cells of interest. Now the why or the how. The how is basically to take a page out of the playbook of envelope viruses. Envelope viruses you may be aware of because they're the progenitor of the lentiviral vector systems that are used for many ex vivo applications. What's shown here is that the way in which these lentivirus vectors and envelope viruses are generated and infect cells, and what we're going to show you is how we're able to use this general approach, this general mechanism of gene transfer to gain absolute cell type specificity. Envelope viruses are produced from infected cells in such a way that they uniquely take off pieces of the cellular membrane with them, and on the cellular membrane are presented viral proteins, envelope proteins, or fusogen proteins, as we call them, that predominantly, almost exclusively dictate the kinds of cells that can be infected. Shown on the right side, the virus particle generated, the envelope viruses, or as we call them, the fusogens, are then able to infect cells solely on the ability of that envelope presented on the surface to interact with a cellular receptor on the cell to be infected. Notably, most envelope viruses have envelopes or fusogens that allow the viruses to infect a wide variety of cells. Interestingly, in the development of lentivirus vectors and retrovirus vectors, it's been possible to demonstrate that you can shuffle these envelope proteins or fusogens. That is, if you express alternate envelopes on the surface of an infected cell, the viruses called viral types that come out of the cell then will have the specificity of the new fusogen. What we've been able to do is to re-engineer viral envelope proteins, so they will have specificity. I'll just very briefly show you how that occurs. People have attempted this for a number of years. In fact, I hate to admit, we tried this maybe 40 years ago in my early days when I knew Steve, I guess, it never worked. We weren't using the right envelope protein. The innovation here was to use a two-part envelope system, a fusogen system, where one component dictates the attachment of the viral-like particle to this cell, and the second component allows the fusion to occur that's necessary for the virus to enter the cells. The reason this is important is many have found through the years, if you use a single envelope or fusogen protein that has to do both of those tasks, recognize the recipient cell and induce fusion, it's hard to kind of change the specificity without mucking up the efficiency of the cell fusion. We've used a exotic paramyxovirus fusogen that consists of a G protein or attachment protein and the F protein, a fusion protein. What we've done to confer specificity upon this fusogen is to first mutate the receptor binding domain of the G protein so that G protein no longer is able to recognize its normal receptor. It can't see anything, so it can't allow infection to occur. What we do is we append to the mutated G protein, a protein sequence that confers the ability to recognize the desired antigen on the recipient cell. That antigen is the antigen that specifies the type of cell that we want to infect. In the cases you'll hear about from Ari, we're talking about very well-characterized antigens specific for desirable cell type, a CD4 cell, a CD8 cell, a CD3 cell. You'll hear later from Ed a more complicated system where there isn't one antigen that you can choose. The point of the story is that basically, although this is designed to give you complete specificity, you're only as good as the antigen that you pick. Next slide just points out that remarkably, I think remarkably anyways, it works extraordinarily well. Well, it's not a plug-and-play system. It's near that. With good protein engineers, which we have, we're able to take a number of different scaffolds that bind desirable proteins and append them to the mutated G protein in such a way that the new protein will both recognize the desired antigen on the recipient cell and still has the fancy footwork necessary to interact with the F protein to elicit entry, cell fusion. I didn't probably make that clear, but normally the way this system works is after the G protein recognizes its receptor, it tickles the F protein in a very sophisticated way that allows the entry to occur. In summary, we have a nearly plug-and-play system. It's very versatile in terms of the types of antigens we can target. I've shown here a list of some of them that are of interest to us. That just shows that we can do this. Takes a little bit of work, we can almost always get things that work very well. Work very well is all about potency. I like to say it's the titer, stupid. It's very, very important to have very potent partners. If some of you go back, the analysts in the audience, and go read papers for the last 20 years, you might say, "Hasn't this been done before? It kind of looks like I see these papers." They're all in human gene therapy if you wanna go look at them. The problem is they just, they don't make the grade. They're insufficient to allow in vivo gene therapy to occur. The system we have. It's so damn potent that it really approaches the kinds of potency that traditional lentivirus vectors like Terry has talked about that allow very high titers and a very efficient entry into cells. Summary, system works extremely well, is specific, applicable to all kinds of things. The final thing I'll point out is really an introduction to Ed's talk, in fact, is that the fusosome platform is very versatile in terms of the kind of payloads that this delivery vehicle can introduce. Some of the issues with AAV as an in vivo delivery vehicle and also LNPs is they're not really amenable to more sophisticated gene editing payloads. They're not necessarily amenable to putting in DNA, transferring DNA. They're not necessarily amenable to putting in RNA, just RNA. Because of the nature of the virus-like particle, very much like a lentivirus particle, and the sophistication about how you generate these packageable virus-like particles, we are able and have demonstrated the delivery of not only DNA, which again is what Terry's next gonna talk about, standard lentivirus-like machinery that allows proviral integrations of cells, but also mRNA protein editing agents and a mixture of all three. There you have it. I'm gonna turn over the mic to Terry, who's gonna talk about the traditional DNA fusosome, and then we'll hear from Ed. Nah, I'm good. You guys can hear me? Okay. I'm actually it's pretty exciting to stand up here and tell you about the progress that we've made in this program. We've been talking about this program for a while, and I think what you'll see is that you know, we're really in a position now to test this, you know, this approach, this novel gene delivery platform, you know, in humans, you know, with a real potential to see, you know, activity. I think, you know, not only, you know, certainly would this be important and critical in terms of, you know, validating, you know, this platform that Richard just described, but I think, you know, if we're successful in the CAR T-cell space, this would certainly be transformative. I mean, this is a novel platform. This could be hard. It's gonna take some time, this would really, really transform the field because of a couple of things. One, you overcome, you know, all the complexities of the manufacturing, with the ability to deliver a CAR gene in vivo with a single intravenous infusion. The other component is that we're gonna do this without lymphodepletion because we don't wanna give the lymphodepletion to damage the T-cells inside the patient. The third element of this, is that because we're not removing T-cells from the body, exposing them to high concentrations of cytokine activation, et cetera, we would expect that the quality of these T-cells would be superior to what you see with ex vivo manufacturing, and potentially would be a reason why we might see activity, you know, even in the absence of lymphodepletion. What we're talking about here is really with a single intravenous injection of this fusosome particle that we deliver a CAR gene to T-cells in vivo, resulting in expression, and then all the activities that we associate with CAR-positive T-cells, you know, with ex vivo manufacturing. That is to say activation, expansion, eradication of tumor. With the initial programs, you know, the gene we'll be delivering is a CD19 CAR, a well-validated CAR, and that's deliberate because really what we wanna do is to isolate the risk of this program on the fusosome itself. That is the ability to specifically and efficiently deliver genes to T-cells in vivo. As Richard mentioned, you know, we've been very successful at identifying fusogens. That is to say the protein that actually allows the fusosomes to target cell types. You know, this is an example of sort of a campaign to identify binders. You know, it is the case, certainly there's a variability in potency. You know, that is to say here in this case, the ability to deliver GFP to cells, this allows us to identify optimal binders. We can also select binders based on cross-reactivity, for example, in non-human primates that allows toxicology studies that I'll talk about in a few minutes. We can then take these binders, put them onto fusosomes, and then package a CAR gene, and then test these in non-clinical studies. This is sort of an example of one of these models, you know, where we're delivering a CAR gene in vivo. The difference in this model is that the human cells that are engrafted in these mice, the human T-cells that are engrafted in these mice are not gene modified, and so these mice then receive a single injection of the fusosome, and then we're able to measure CAR T-cells and CAR on the surface of these T-cells. By gating on the different, you know, T-cell fractions, CD4, CD8 positive T-cells, we can demonstrate 2 things. 1, specificity, since we don't see evidence of CAR gene in the CD4 positive compartment, and the 2nd is that we deliver genes to CD8 positive T-cells in a dose-dependent manner. We can then look at the ability for these cells to eradicate tumors, and what we find is that across multiple donors, we've done lots of these types of experiments with multiple CARs. You can see that the CAR T-cells are highly functional and able to control tumors the same way as ex vivo CARs. I will point out that as 1 might expect, the kinetics of this is a little bit slower. It takes longer to see control of these tumors, which is expected because we've got to generate the CAR T-cells inside the mouse. The binder that we've selected for the lead program, 299, cross-reacts a non-human primate CD8, and so again, it allows us to do non-human primate studies. We've done a number of these studies. This is an example of one of those studies with an earlier manufacturing process, in which we were able to demonstrate depletion of B cells. Importantly, the reason this is a CD20 CAR is because the CAR, the CD19 CAR that we're utilizing doesn't cross-react to non-human primate B cells, so this surrogate allows us to measure pharmacodynamic effects, that is to say B cell depletion in these animals. What we see is B cell depletion in a subset of the animals, 4 out of 6 of the animals. Importantly, when we looked at later time points, this is immunohistochemistry for CD20 positive B cells in secondary lymphoid tissues. We see sustained depletion lasting out in this necropsy in this animal shown on the right, was done at almost 60 days after fusosome infusion. The other thing that we're able to do is to use in situ approaches to actually directly measure CAR gene in secondary lymphoid tissues. What I'm showing on this slide is lymph node biopsies since day 9, and then spleen at day 35. You know, CAR's detected using two different imaging modalities, standard IHC, the brown, and then immunofluorescence where you see the red CAR positive cells in these tissues. What you see is evidence of CAR positive cells or gene transfer in secondary lymphoid tissues, day 9, day 35. Importantly, we have not seen, using this particular modality, evidence for CAR gene in liver, an organ that we would expect to see, you know, large amounts of the systemically administered fusosome. The other thing we can do is use co-staining to confirm that the cells are CAR positive or actually the target cell type that we're going after. This is an example of one of those staining protocols, where we can demonstrate, you know, the red on the far right there, which is the CAR gene, localized to the CD8 positive cells within these secondary lymphoid tissues, again demonstrating specificity. As Richard mentioned, you know, it turns out that it's difficult to make this material at very high concentrations or potency. One of the areas that the manufacturing folks within Sana have spent a lot of time working on is improving the manufacturing process. They've made really outstanding progress in this has resulted in improvements in really three different areas, you know, potency, yield, and purity. A lot of the impurities, you know, in the product, you know, comes from the producer cell line, both host cell DNA and host cell protein. Importantly, you know, this has now been consistently observed and observed at scale, you know, 200 liter bioreactors. You know, we're seeing, you know, 50, you know, plus X improvement in titers. I want to take a moment here before I go to the next slide and just remind everybody that Richard talked a lot about potency as being the most important element here. For the drug product, the potency is defined as, you know, the ability to transfer genes into cell lines, right? That's an analytic that needs to be done to actually measure functional particles. The important component that you want to then look at is how does that functional potency defined as transfer into cell lines translate into transfer of genes into your primary cell of interest, in this case T cells. You know, what we've seen with the manufacturing improvements is at a given dose, in this case defined as a concentration of particles, per T cell, we actually see improved gene transfer with the new manufacturing process relative to the old manufacturing process. That's shown on the left across a range of IUs per PBMCs, and then on the right across five donors, at a single MOI that, or IU per cell. Again, with both the improvement in titer, the potency of the drug product itself, and the improvement in gene transfer efficiency, we're looking at a couple of things. One, you know, because of the 50x improvement in titer, it means that we can deliver the same amount of functional particles in proportionally less volume, right? Which is critical in terms of dosing patients. The second thing is that, you know, we see improved gene transfer efficiency. Collectively, right now we're estimating that we can, you know, potentially generate equivalent numbers of CAR T cells to what you see delivered with ex vivo CAR T cell manufacturing. We're on track to file an IND for this program in 2023. The manufacturing runs are underway. The GLP toxicology study in non-human primates is on track for completion. The phase I study in which we'll go after acute lymphoblastic leukemia as our first indication has been is in the planning stages. Again, I already mentioned that last bullet point that we're, you know, we're anticipating that we're gonna be able to deliver comparable CAR T-cell dose to ex vivo manufacturing. You know, just very quickly, I'm gonna walk you through some areas that we're looking at beyond this program. Certainly, you know, interested in targeting other T-cell receptors or other T-cell types, delivering other payloads or different CAR genes. You know, certainly, you know, thinking about the potential here, in autoimmune disease where, you know, one might expect to see, you know, biologic activity, we already know that the CAR T-cell dose with ex vivo CAR T-cells seems to be lower. There's a potential that we actually might see that autoimmune disease might be an optimal place to take this after we'd certainly generate safety and data in humans. Just quickly, you know, this is just, you know, data demonstrating that we can deliver CAR genes to other T-cell types in the same mouse model that I described earlier. In this case, using a CD4-targeted fusosome, demonstrating that, you know, CD4-positive CAR T-cells are able to eradicate tumors in this mouse model with NALM-6. Second, thing that we've looked at, and not a surprise that we can swap out the genetic payload, deliver other, you know, CAR genes, in this case, you know, a CD22 CAR that I've already described earlier in the allogeneic program, and demonstrate the ability to control tumors in these animals. In terms of upcoming milestones, you know, we've demonstrated the ability to deliver genes specifically, you know, into CD8-positive cells, with minimal evidence of off-target effects. We've shown tumor clearance in the preclinical models across multiple models and multiple donors. We haven't seen safety concerns in the non-human primate studies we've conducted. We've seen, you know, market improvement, in potency, and the ability to target additional T cell subsets and to deliver different CARs. We're on track now to file an IND, this year, you know, with the expectation that we'll be able to generate early clinical data next year. With that, I'm gonna turn this over to Ed Rebar who's gonna close this out. Great. Thanks. Coming through? I hope you all enjoyed Terry Fry's talk and are as excited as we are about our ability to generate CAR T-cells in vivo. We've been very pleased with the performance of our fusosome platform for doing this high efficiency gene transfer. Our aspiration is to go beyond that as both Richard and Steve indicated in their talks. What Sana aspires to is the ability to do genome editing therapeutically in vivo. Apologies. What that means is basically the ability to go to a patient, go to a chosen cell type, point to a spot in the genome and say, "We wanna make this precise change right there," and that's what this slide indicates. If we could do that, right, we could open up a wide variety of new types of indications that we can go after, and also we could take current indications, so there's a small number that other entities are addressing that are being performed ex vivo, and bring them into the in vivo setting, where you could dramatically improve patient access. This ambition is not without its challenges. Pardon me. I'd say the three key ones are indicated here. Those are achieving cell-specific delivery. This is critical not only for safety, but also potency and manufacturability, and I think Steve Goldman and Richard Mulligan did a great job of describing that earlier. Also delivering the appropriate payload type, right? Gene editing can require delivery of protein, RNA, DNA, or some combination of those entities, and also delivering sufficient editing reagent, right? Ideally, what you'd like is for one delivery event, one unit, a particle or a virus, to be able to reliably edit that targeted cell. What's really exciting about fusosomes is that they seem to have the capacity to address all of these considerations, right? In terms of achieving cell-specific delivery, Richard described very, very nicely, how we're able to retarget fusosomes to go to cells of our choosing, and I'll provide some data in a few slides showing how we can make that be a very highly specific delivery event. In terms of delivering the appropriate payloads, type, fusosomes have the inherent capacity to package both RNA and protein, and by virtue of this natural process of reverse transcription of the packaged RNA, DNA as well. They just inherently allow you to deliver any type of molecule you might need for in vivo editing. Finally, in terms of delivering sufficient editing reagent, fusosomes have a size and a capacity that's larger than other options, which allow you to deliver more editing reagent as well as larger gene templates that might be available, say, via AAV. I'm just gonna spend a couple of slides on making maybe a little more clearly on how gene editing fusosomes differ from integrating fusosomes. Basically at top is the integrating fusosome. This is kind of the archetypal parental fusosome. This is what Terry described in his talk. These particles are very good at integrating transgenes randomly in the genome. On the bottom is gene editing fusosomes, what those are specialized for packaging and delivering gene editing reagents. What they offer is the capacity to make specific edits at chosen sites in the genome. It's this capability that allows them to address potentially a much wider range of application types. I don't wanna disparage the parental fusosome. It's actually very good at what it does, and if you wanna do something like make CAR T cells, I think it's the best platform around. If you want to do something more site-specifically, like knock out a specific gene or correct a chosen mutation in the genome or integrate a transgene at a known location for some purpose, what you'll want is a gene editing fusosome, and you'll have the capacity to do more useful therapeutic things. Okay, with this rationale, Sana has begun adapting fusosomes for gene editing, and we focused initially on nucleases and base editors. I think those are the most advanced editing reagents for therapy application. Here's an early study where we just tested our ability to package these reagents in fusosomes. The experiment was, we ran a production run, took some of the sort of crude, unpurified supernatant from those producer cells containing the fusosomes, and then titrated these reagents onto tester cells just to see how well we could either edit in the case of nucleases or convert a base in the case of base editors, those target loci. These are the resulting titration curves, and this indicated that we can make very highly potent particles. It's not shown on this slide, but if we ran a similar study using our integrating fusosomes and just asked for gene transfer, we can generate highly similar curves. We do well relative to that benchmark. We've also taken these fusosomes and have started performing in vivo studies with them. This is one early such study where we looked at knockout, our ability to knock out the TTR gene in human cells in a mouse model bearing a humanized liver. So the model is sketched out on the left. The study overview is provided on the right, and the really critical aspects of the study overview are that we tested two different types of fusosomes, one carrying a nuclease targeted to TTR and one carrying an irrelevant nuclease that was the control. We tested them in these humanized liver mice, providing them on day one of the experiment, and then at day 17, looking at the gene modification in the liver cells as well as the secreted levels of this TTR gene product in the blood. The results are shown on this slide. On the left, we're monitoring gene editing percentage via sequencing, and we're able to show a very high level of editing, 55% in the treated mice versus mice treated with our negative control fusosome. On the right, we monitored the level of transthyretin, this is the TTR gene product in the bloodstream. You can see at day 0, the pre-bleed mice, there was no difference in levels, whereas at day 17 we see in the range of 60%-70% repression or a reduction in that level of TTR. That's consistent with our gene editing efficiency, and was a really nice result for this highly early study. Okay. Now I should mention at this point that, you know, this was a good model system to perform our initial in vivo studies in, very convenient to test these reagents, but TTR is not a therapeutic target for us. We then transitioned our focus for our in vivo studies to what we are endeavoring to make therapies in, and that's HSCs. HSCs or hematopoietic stem cells are a very important stem cell type in your blood compartment. They give rise to diverse progeny that comprise the blood and immune systems as well as some other cells. Given their critical role, methods for efficient editing of these cells have the capability of potentially addressing many different types of diseases. This is just a partial list on the right-hand side. I should mention that many of these diseases are in fact being addressed at this time or there are many entities endeavoring to address these diseases using ex vivo methods. What we wanna do, of course, is to do this in an in vivo fashion. The reason for this is highlighted on this slide. I think actually this has been pointed out several times by prior speakers. Basically, an ex vivo process is much more cumbersome than an in vivo process. Moreover, there's substantial safety considerations given the conditioning that's involved for ex vivo therapies. We're very excited to pursue this vision. I just want to point out that Sana has these diverse but necessary capabilities that you will need in order to be successful here. We have fusosome expertise, a team that's been working together for five years to design and retarget fusosomes to cells of our choosing. We have genome editing expertise. This involves both the development of therapeutic editing reagents as well as their qualification for IND filings. We have HSC expertise, both deep knowledge of the receptor biology that you'll need to know in order to target HSCs. Richard alluded to this. It's an area that you really need to know what you're doing in order to focus your modification on HSCs or cell compartments that contain HSCs, and also the uses and limitations of HSC preclinical models. Finally, we've licensed foundational IP. With that, I'll close out by just providing three data slides that I find tremendously exciting and that I think give a sense of our capabilities at this point and where we're heading. First of all, we've shown that we can make editing fusosomes and efficiently modify CD34 cells, and this is just an example of that. It's a slide very similar to the one I showed three slides ago. Fusosomes were made in producer cells applied to tester cells. We got very high efficiency editing of our target gene B2M, but in this case, the tester cells were CD34 cells. We then took these fusosomes, and we've tested them for the ability to modify bone marrow cells in vivo. An overview of the study model is indicated on the left. Excuse me. This is a mouse model that allows ready engraftment of human CD34 cells. This mouse model is treated with the CD34 cells. After seven days in the engraftment, it's then treated with fusosomes, and after another five days, we look at either all the bone marrow cells in those mice or just a subset that's thought to be enriched for HSCs, and we see how well we're doing for the modification. Those results are indicated on the bar charts on the right. What we're able to show is that, we're able to modify in vivo, anywhere from 20% to 40% or even close to 50% of the targeted cells, indicating a very high degree of potency in this in vivo setting. Now, I should point out that, you know, we can't formally say we've targeted the HSCs. You have to do a longer term study in order to prove that definitively. We're very excited by our ability to get to the cell type that, we expect will include that HSC compartment. Finally, this theme of safety and specificity has been highlighted multiple times throughout this series of presentations, and it's in this context that I find this last slide to be the most exciting one, at least for my section. In these prior studies that I've just talked about, you know, we achieved important proof of concept targeting CD34 cells and targeting bone marrow, but that was with fusosomes that were actually somewhat broad in their tropism. They hadn't been refined to be pinpoint specific for just a minor type of cell. In this study, we took fusosomes that actually had been engineered to target a very precisely chosen compartment of cells. This is the cells represented by that blue sliver in that right-hand pie, right? If you took the whole set of marrow cells, you could point to a particular type identified by expression of a chosen receptor, and that would be that blue sliver. We said we wanted to target just those cells. The fusosome team generated fusogens that were specific for that receptor, and we tested that fusosome type in these mice. The results are shown in the bar chart at bottom. We were able to show that of that 0.4% sliver, we were able to get 7% of those cells successfully targeted. Whereas for that remaining 99.6%, that bulk of the cells, the remainder cells in bone marrow, we were able to largely avoid them having gene transfer to them of only 0.04%. Basically, we were able to show a 180-fold preference with this targeted fusosome system. I just wanna, you know, underscore that what does that mean, right? That translates directly if you're worried about, say, safety, right? The ability to suppress gene delivery to all the other cells you might get into by more than 100-fold, that directly translates to enhanced safety. In terms of potency or manufacturability, right? That means that you have 100x more potency for the cells you want. It means you have to manufacture that much less. This is actually a very important result. Finally, just as a control, I should point out that we tested our non-targeted fusosome and saw the expected no cell preference. Just to summarize, a lot of exciting progress. Wanted to highlight where we're heading. The next is to develop gene editing fusosomes for a therapeutically relevant gene. We're also headed towards non-human primate proof of concept, as well as filing an IND for an in vivo therapy, likely in the β-globinopathies. With that, I think we go to Q&A. All right. Thank you, Ed. Thanks, everybody, for the attention. We kind of went through a lot today. Hopefully, you were able to see a little bit about why we're so excited about the technologies we've put together, the data we've generated, and our ability to translate those hopefully into important medicines for patients. You know, we're on the precipice of really understanding how well the preclinical data that you've seen translates into people. With that, we're gonna open it up for questions, and I'll just be joined on stage by our scientific team. Any questions? If you just wait a second here, Nikki will come with a microphone to make sure that, A, I can hear you because I have bad hearing, and more importantly, people on the webcast can hear you. Thank you. Salveen Richter-Goldman Sachs. maybe to start here on CD19, is there a possibility of de novo generation of mechanisms that could down-regulate CD47 expression in lymphoma patients and lead therefore to decreased persistence or an allogeneic reaction? I have a follow-up to that. Terry, you wanna take that? Yeah, sure. I wanna make sure that I understand exactly what you're talking about. You're talking about de novo downregulation of 47 on the lymphoma cells? Yes. Yeah, I mean, I'm not aware of any data to indicate that that's happening. I mean, I, you know, but, you know, certainly, you know, something we'll have to pay attention to, but I'm not aware of that happening. To the extent that it did, I can't imagine it would be. Yeah, I was trying to think that one through. it would be important for what we do. Yeah. To be clear, CD47 has nothing to do at this point with how we target the cancer cell. Right. Right? It has nothing to do with the interaction at this point, although Terry showed you some data, between the CAR T-cell and the tumor cell. What it has to do is with how we prevent transplant rejection of the patient's own immune cells from killing the CAR T-cell. Variable expression on the target cancer cell should have zero impact. We don't have SIRPα, the cognate receptor, on the other cells, so it shouldn't impact it. Can you just speak to the translatability of the HIP modifications to humans? Just your thoughts on how that'll translate from the animal studies. Is that for Terry, you think? Or... Sonia. Or- Sonia. Sonja. I'm not sure I got the question. Did you get the question? Translate? You're talking about the in vivo delivery? On CD19. The HSC. Sure. On CD19, whether you can talk about the translatability of HIP modifications into humans? Yeah. I mean, the models we showed you, those are used in the, in the field, in the CAR T studies. I think what's different about our studies is that we not only use NSG mice, which don't have an immune system, we really use also humanized mice. Showing you that allogeneic barrier and how to overcome that, I haven't seen that in the field when I look at preclinical data from others. Also, they might have allogeneic strategies. They still studied in immunodeficient mice. I feel we at least have this component of an allogeneic barrier in. Also the follow-up, if you look at our data, we have a quite long follow-up of 3 months. The tumor study I showed you with the re-challenge. Of course, it is a preclinical mouse model. I cannot think about any more closer to the clinic than what we showed you. I think we have to see. Thank you, Sophie. Thanks. Brian Benjamin from JMP Securities. I guess just one, you know, starting off, can you talk a little bit about the donor cell characterization and how you're picking these cells? You know, is there, you know, the criteria that you're using so that you're getting this, you know, type of homogeneous product. Along with that, on the patient side, is there variability of expression of, you know, either CD47 or sort of alpha expression, right, that might make you think about, you know, the ideal sort of patients to select when running these clinical studies? Terry, do you want to take the first one and maybe Sonia, you take the second? Does that make sense? Yeah, sure. I guess, I wanna make sure I get the first question. If you don't mind just kind of repeating that for me, just so I understand. You're taking healthy donor cells. Yeah. donor characteristics. Yeah. Got it. We haven't, you know, what I would say is that we definitely recognize that when you make CAR T-cells from cancer patients, right, that there's, you know, variability in quality. You know, a lot of that, you know, driven by the therapies that those patients have received. We also recognize that there's, you know, a lot of donor variability, even with healthy donors when you run sort of the preclinical models. We're looking very carefully at product quality relative to donor characteristics. I wouldn't say that we or I think anybody else in the field are at a point where you can, you know, select the super donor, so to speak, that everyone is talking about. It is something that, you know, we're spending a lot of time looking at. There are other selection criteria that we utilize, you know, that are relevant to the hypoimmune platform itself that, you know, we incorporate into our donor selection. To maybe just put a pin in that, a big part of the rest of development once you have early evidence of immune evasion and complete durable response rates, you know, one of the more important elements of proving we have a really viable, scalable drug is to be able to look at multiple donors, right? Even as part of our phase I study, it will be to ensure we can control that donor-to-donor variability and have a predictable safety and efficacy profile for a drug product. It's also one of the reasons why we have so much drug on our shelf available for autoimmune disorders, because even just to run a phase I study, we will have multiple manufacturing runs with a lot of drug product that's ready to go. Sonja, you wanna take the second part of that question? Yeah. The second part was the SIRPα expression, if that varies between different patients on the NK cells. We've studied that for many, many years, and what we have found is that everyone, when you look at primary NK cells, all the NK cells are expressing the SIRPα. When the NK cells get activated, they're even up-regulating it. We published that 2021 in our Nature paper. We haven't found any patient population where NK cells subpopulations wouldn't express the receptor. That being said, if you look at NK cell lines in papers, then you see that NK cell lines are not expressing the SIRPα. If you would do our assays with lines, and they are derivative from tumors usually, then the CD47 axis wouldn't work. It is not relevant for the patient because what is important is the primary NK cell population in the patients. The only NK cells I have seen where there is no SIRPα are the lines from the tumors. One of the real challenges of the field, unfortunately, historically, people have used these cell lines for NK cells that have been derived from tumors, and that's really been misleading for people. It would be a little bit like trying to you know, study lung function from a lung cancer cell. Intuitively, it doesn't make sense, but unfortunately, the field had done it for a while. Really moving the field forward by testing primary NK cells is imperative. Okay going forward. Hi, Emily Bodnar from H.C. Wainwright. Curious if you can discuss a bit more about the safety that you've seen in preclinical studies, particularly in NHP studies, and if there's been any evidence of things like infections, CRS, neurotoxicity, then I would follow up as well. Okay, Terry, you wanna take that? Yeah. The simple answer to the second part of that question, you know, with the CAR T-cell delivery in the NHPs is we've not seen, you know, CRS. I mean, you know, the model that we're using, the CAR that we're using is one that, you know, has been used, you know, to test CAR T-cells in non-human primates by, you know, Leslie Kean, Mike Jensen. You know, but in that particular model system, I mean, you know, the monkeys received lymphodepletion and really high doses of CAR T-cells. They did see toxicity. It is possible to see toxicity in the non-human primates. We didn't see any. We did see evidence for inflammatory activity based on elevations to cytokines, et cetera, in the animals. Hi, this is Taylor Hanley from J.P. Morgan. I had a question about the IST data that we're expecting later this year. What duration of treatment can we expect to see, and how durable do the islet cells need to be in order to establish proof of concept here? Just if you could provide any color on any other benchmarks you're hoping to hit. Thanks. Hey, Doug, you wanna start with that one? You know, Sonja, if you have anything to add, feel free 'cause you've been. Sure ... intimately involved. Yeah, I think the durability, you know, that issue will be solved fairly quickly, right? Because we know that in the transplant field that the acute rejection, the allo rejection would take place in a matter of probably several days. So that's a very rapid process that I think we can look at and monitor early on in the course of the study. I think some of the other endpoints that we're looking at and things like C-peptide will take a little longer, probably on the order of weeks. I'm looking at you for confirmation there, Sonja. You know, I think we'll get some insights very quickly on the persistence question, and that it'll take a little longer for some of the other more physiologic endpoints I'll call them to manifest themselves in these patients. Yeah. I agree with that. The hypoimmune team, we will start celebrating after, like, 2 weeks because that would show me that we overcame that allogeneic barrier which you expect to happen really fast as Doug said. Of course, we have to wait a little bit longer than for the C-peptide. Hiya. Asim Rana from Truist Securities. Just wondering in the cryopreserved islet cells, if you could talk about the cell quality post-thaw and any assays you might be doing? In the absence of what? I'm sorry. Any assays that you might be doing. Doug, I'll let you take that at a high level, but we might wanna be a little careful about exact assays. I think there's a whole battery of assays that, as you can imagine, are looking at product quality. We haven't talked too much about the specifics around that, but I think you can sort of look at some of the data that we've generated, you know, handling these cells, transplanting these cells, and looking at the performance that we're seeing with respect to their ability to generate C-peptide levels and insulin production in the experimental models. I do think that we feel very confident about, you know, the quality of the cells that we're producing and their capacity to actually do the job we're asking them to do in the transplant setting. It's a really important question, a couple of reasons why. First off, if we can't cryopreserve these cells, we obviously we're not gonna be able to scale either manufacturing or distribution for patients. The second, you know, in multiple settings, what we've seen is that, you know, cryopreservation can impact cell quality, and I've had some experience with that in a past lifetime. It is something we need to be very careful about. The third is these cells actually need to exist and be transplanted in a cluster, right? Not as single cells, which makes it more complicated. You know, we'll share more on that going forward. It's, it's a spot on question, and we'll make sure to kind of be, you know, more and more transparent, but it's very important. I have a question from the webcast that I'll read out. Sonja, this is for you. Could you share more color on your non-human primate model for type 1 diabetes? You know, specifically, STZ dose and/or just any potential that you see for regeneration of the host islets. Yeah. It's a good question. Yeah. That's a great question. Important question. Yeah. Yeah. It took us a while to establish that model. We used the high-dose STC. It's a one-shot treatment. High dose, I think it was 100 kgs mix per kgs. We used the dose out of a publication where they had studied hundreds of cynomolgus monkeys and how to induce diabetes because you could also give multiple doses, lower dose. We chose the high dose one time because according to that publication, it had the best effect. We cannot really have a good look at, of course, the endogenous pancreas if that repairs over time, but I have showed you the C-peptide data. You see on the day of the hypoimmune transplant, the C-peptide was down. 7 days after the transplantation, it was in a normal range. That occurred because the pancreas miraculously renated or restored during that time is highly unlikely, but there is not a good way for us to really show you those data yet. What we would need to do is taken out the pancreas and have a look at it, but the experiment is still ongoing, so we don't have any of that information. Yeah. It's one of the reasons there's a long period of time between day 0 and the transplant at day 78. It's hard to imagine if you're 0 at day 78 that it's regenerated itself afterwards because that has been something that's shown up in other experiments. A question in the back. Hey, Michael Schmidt with Guggenheim. I might have missed it earlier, for SC291, when do you plan to launch the studies in autoimmune diseases? Do you feel like you need to get experience in a cancer study first before starting that, or do you wanna launch into that right away? Doug, you taking that? Or you want me to? Yeah, I think as you heard, you know, we're basically in a position where we have drug available. We're right now in the process of really sort of refining the basket, as I referred to it. Obviously, that would include lupus nephritis, I think as one of the sort of pathfinding indications based on the previous data. We do wanna think carefully about the other indications that we try to pursue. I think, you know, there are other groups that have announced their baskets. I suspect that there'll be, you know, some differences in the composition of the diseases we focus on. You know, we're being very careful about the choice of those diseases initially. I think it's also possible that we'll think about sort of a multiple basket approach, with more than one collection of diseases focusing on potentially other organ systems. Very much in process right now to define the protocol and the path forward. We're in a position where we can move very quickly given that we've got drug and are sort of well down the path with an existing IND. One of the challenges of autologous CAR T-cells is that patients have received multiple different previous therapies that can meaningfully impact T-cell quality and therefore the ability to make a CAR T-cell, right? You've seen this in the blood cancer field where, you know, there are modest differences in the manufacturing processes across different indications. As you move forward with an autologous CAR T-cell in autoimmune disorder, there's likely gonna be a necessity to show that the process you have works for patients with those diseases. One of the advantages of an allogeneic platform is, again, if this works as well as we hope it does, is that we have a single donor quality, right? That we can utilize, and it can work across multiple different disease types. We don't have to worry about that. Off-the-shelf drug that's already sitting there, already manufactured, can be utilized across multiple different patient populations, which allows us to move in clinical development at a pace that might not be possible for in other settings. Hopefully, when we get to commercialization, it gives us a scale that allows us to really go after this. I do believe we're at the top of the hour, and I don't see anybody's hands, you know... We do have one more question. We have actually time for one more. We'll do that. Thank you so much for squeezing me in. This is Hao for Jefferies from Bank of America. Maybe a question for Fusogens. A little bit on the off-the-target effect, in term of, you know, for you delivering a CD8 targeting CAR. If it's off-target, what could be the challenge that happens? You know, given you have so many choice of targets and so many choice of things that you can deliver, how you prioritize in your pipelines for future products? Thank you. Terry, you wanna take the first one? Yeah, sure. I guess you can think about off-target in a couple different ways. One off-target would be sort of an on-target/off-target, that is to say non-T cells that express the non, you know, CD8 positive canonical T cells that express the target receptor. You know, with CD8, what you would expect would be things like natural killer cells, you know, NKT cells, et cetera. Don't necessarily mind delivering obviously a CAR chain to those cells 'cause they could have therapeutic activity. You know, I think the thing we've really spent a lot of time digging into, and you heard with a number of the presentations, is really understanding true off-target delivery. That is to say, delivery to cells that don't express the target receptor. You know, thus far, I mean, you know, we've seen, you know, vanishingly low levels of gene transfer into other cell types. I showed you the in situ data. We've also looked via PCR, et cetera. It's something we're spending a lot of time looking at for sure. I wasn't sure, was the latter question all different ways or within the CD8 target fusosome? All different targets and all the, you know, DNA, everything that you can deliver. Yeah. Maybe I'll just take a little of that just to start. I mean, there are two elements that we have in targeting. One is the volume of distribution of the fusosome, right? We can change the fusosomes, but when we start with a fusosome that has a limited volume of distribution, right? That is both a feature in that it enhances our ability to really drive specificity, and it's a little bit of a bug, right? In that you can't get to every cell type. We start with the cell types that we know are accessible, and then we look to see where would, you know, having a targeted delivery capability be very valuable. I like to always think in terms of risk baskets, right? With a new platform, you've got platform risk, disease biology risk, clinical trial risk, and kind of commercial risk. Go after high unmet needs where someone else has already figured out how to, you know, what the right endpoints are in a clinical study, and where there's proven disease biology so that we know if it works, it, you know, if it doesn't work or if it works, it's because of our platform. That's one of the reasons we think HSCs are such a viable target at for initially delivering, you know, gene-specific modification because the field's done a wonderful job of showing that that can have a profound benefit for some patients. We would love to be able to expand the accessibility of that both by eliminating the need for myeloablative, you know, bone marrow, like, chemotherapy, which has to really be delivered not just in the inpatient setting, but monitored in the inpatient setting for a while, and also with an easier manufacturing. That's a little bit how we got there. That, I think, was the gong that said we were done. Really appreciate your time and, energy and attention today, and I look forward to, you know, continuing our conversation going forward. Thank you.