In vivo reprogramming of T cells, I think, is really coming within our grasp, for therapeutic deployment. The same then is true for sickle cell. So redosable in vivo editing in this case, because remember, HSCs differentiate to create the series of lineages that are important across a whole host of blood-borne cell types. So here you need to edit the HSC in order to create the same kind of in vivo advantages of being point of care, expanding patient access, and dispelling what the kind of ablation approaches that are required for ex vivo. Like I was saying, for the ex vivo T cell world, which will be dramatically expanded by having access to in vivo dosing, we think the same is true for HSCs, dramatically expanding access for sickle cell and beta thal, but also driving the potential to expand into a variety of hematology disorders and ultimately biofactory applications. Lastly, for hem A, as I mentioned before, here the delivery is to hepatocytes, and here the cargo is our iqDNA. This is a form of DNA that evades immune detection and allows for long-term gain of function, in this case, for factor VIII. Lots has been said about what's happening in hemophilia A, so just to say a couple of words about where that market is going and why this approach, I think, represents such a huge step forward in the future. So the axis of hemophilia evolution has occurred across primarily these dimensions of coverage and duration. So the advent of long-acting hemophilia factors and bispecific antibodies have allowed for the basal level of coverage to approach 15%, and that's a level of factor VIII replacement where patients effectively do not experience bleeding. And so that lower bound, if you will, of factor VIII replacement at 15% is quite good, and I think that sets the bar for any new therapy, and it would certainly be a bar we'd be aiming for. Maybe it can be 20%, maybe it can be 25% or greater. What's really important is how long patients can live free of the risk of bleeding, and today the outer bounds for that limit is about two weeks. Maybe with second-generation bispecifics, it can get to a month for many patients. Our profile would be aiming for every 3-5 years of real freedom from hemophilia in a modality that can be redosable, and also one that can be accessible on a global basis. Here, too, we see the technology driving expansion of access from beginning with hem A to moving to a broader set of lysosomal storage disorders, as well as IMs, all on the basis of being able to bring gain-of-function cargo to hepatocytes. These are the three areas we're working in, in vivo access to T cells and HSCs, and then also delivering iqDNA for the treatment of hemophilia and a variety of other genetic diseases. So, maybe I'll leave the intro there, Rick, and then I will come over, and we can chat Oprah style. Sure, sounds good. Thank you. Careful walking through the maze of chairs. All right, so I'd like to begin the conversation on just a pretty high level here. So if we think about the genetic medicine space, delivery has been a pretty large problem for decades now. If you can maybe go into why this has been such a tricky problem to solve, the delivery question, and what are the main innovations that Generation Bio has made on the LNP front to help solve these challenges? Yeah, so, maybe just talk about why delivery is so important, other than tissue or cell-specific access, which, of course, is super important. I mean, a new tissue gets accessible systemically, maybe once a decade, you know, liver. We're living in the age of muscle. Maybe lung is starting to open up in certain delivery modalities, and CNS, of course, have been a holy grail for a long time. What you want from a delivery system, other than tissue access, is you want it to be highly selective, to manage off-target side effects or unintended impacts of on-target and off-target cells. And the selectivity can potentiate real potency, which for genetic medicine cargo is essential. We've seen many genetic medicine cargo programs bump up against the therapeutic index limits of the delivery system before a level of potency has been reached for the cargo. So I think that's just to say at a high level, what's important about delivery. So LNPs at their base are very, very effective and attractive for two reasons. One, they don't induce a systemic immune response, so they're redosable. And two, they actively drive delivery of their contents into the cytoplasm through endosomal escape. So those are two very, very good things about LNPs, and of course, from an industrial perspective, they're quite efficient to make. What's bad about LNPs is that they have completely passive biodistribution. 99% of every administered dose ends up in the liver or the spleen as a result of the fact that LNPs become opsonized. They bind serum proteins when they're administered, and those proteins drive delivery in the good therapeutic sense to the liver, but if you want to get to tissues beyond the liver and the spleen, you have less than 1% of the dose available to do that, and for traditional LNPs, you have a half-life measured in minutes, 8-10 minutes in systemic circulation, because those LNPs are being cleared so rapidly by the liver and the spleen, so to answer your question, what have we done that's different in LNPs? We've re-engineered the base composition of our LNPs to avoid that binding of serum opsons. We are delivering less than 1% of the dose to the liver and less than 0.1% of the dose to the spleen, and extending that half-life to 8+ hours in non-human primates. On that basis, with a large circulating pool of LNPs beyond the liver and the spleen, we're using small format antibodies to drive the engagement of that circulating pool of LNPs to specific cell targets, starting with T cells, and now we're in development for HSCs. That is a situation where we hope to open two new tissues for very selective LNP delivery, T cells and HSCs. Right. Understood. So one of the novel aspects of your LNPs are the extended half-life and the pretty substantial detargeting of the liver and the spleen. So I guess one of my immediate thoughts when you think of an extended half-life LNP, are there any safety concerns there if you have an elevated level of LNPs in the blood? Could you tell us what you've seen preclinically there on the safety side? Yeah, great question. So, I should say to begin with that, as I was referring to earlier, the selectivity can allow for great potency. So when we talk about a larger circulating pool of LNPs, it's not occurring at super high doses. So what we've shown pre-clinically is that we're able to transduce all circulating and spleen-resident T cells that express our receptor at doses of 0.5 mg per kg, and we get to half of all those T cells at 0.05 mg per kg. So we're not talking about high systemic doses of LNPs, it's just proportionate to the dose. You have a lot of circulating, resident, LNP available. In mice and in monkeys, we see a tolerability profile that looks very good, including no LFT elevation or cytokine or complement activation with the system. Okay, when you think more around the dynamics of these LNPs, so, you highlighted T cells and stem cells as targets. Just how quickly can these LNPs be taken up by the target cells, when we think about the extended half-life in the blood at the same time? Yeah. So the transduction occurs quite rapidly. We. I think most of the data we've shown is at 24 or 48 hours. And, you know, obviously then, the impact of the therapy on the target cell type depends on the duration and the impact of the cargo. But the LNP is broken down in serum and then eliminated. All of the components are biodegradable. Okay, and if we think about the range of potential tissues that could be targeted here, I know, the lead programs are focused on, the specific cell types, but what's needed to target a specific tissue? All you need is a good target, specific target that is expressed externally on that cell type, and you could target it with an antibody? Or could you just maybe talk about the range of potential tissues? Yeah. You can, you can move into? Sure. Maybe the most important thing is what you said, is that you have a restricted set of cells that have a restricted set of receptors, which is what drives the selectivity and on-target performance. The other thing to consider is, where are these cell types? So T cells, and to a lesser extent, HSCs, but certainly B cells or NK cells or mast cells, they have a spectrum of either being in the circulation or being accessible to the circulation, and that's what makes some of these cell populations so attractive for targeting. There are certain cell types that have a degree of physical privilege from circulation. Skeletal muscle cells, for example, sit behind very tight junctions in the endothelium, so they're relatively less accessible than, say, vascular endothelial cells themselves. So we've always thought about the blood-brain barrier as a challenge for CNS. I think these tight junctions have historically been a challenge for skeletal muscle, but there's a huge variety of cells that are either in the circulation or in the marrow, or easily accessible to the circulation, that today are not druggable or not accessible in a selective way. Understood. And the LNPs still are in preclinical development, so I was hoping you could maybe elaborate on where we are in preclinical development, what animal models? Yeah ... the LNPs have been evaluated in, and what some of the next steps are for developing these. Yeah. Because what we're doing here with these antibodies is developing them against uniquely human receptors, the initial work is all done in humanized mice. Then, ideally, we're working with ligands that have some degree of cross-reactivity to primates, and we're working in primates now with the T cell delivery system, and we'll release that data when it's available. That really will mark the point at which the T cell delivery system is really ready to advance into development. As you know, we are sharing or apportioning the ability to develop that T cell delivery system with our partner, Moderna. We will be each announcing and describing what we're intending to do with the delivery system as we share the primate-based data that can confirm elements of the biodistribution and some of the PD components that we were referring to. Okay, and that's a great segue for what I wanted to talk about, the collaboration with Moderna. Sure. Mm-hmm. So I was hoping you can go a little bit more into details here on the structure of this partnership. I know you're both working on delivery to T cells, but do you both have separate programs, or are you both gonna advance a program together in collaboration? Could you just talk about- Sure. How that might play out? Sure. In principle, the idea behind the collaboration was to build on our core intellectual property around the stealth LNP and work together to create a series of targeting ligands to get to T cell populations, whether broad or subset populations or both, and on the basis of that delivery system, allow a set of programs to proceed for Moderna, primarily focused on the delivery of messenger RNA. They have a narrow set of rights where they can use our proprietary cargo, iqDNA, within a pool of named targets, up to two programs in T cells. For other cargo, non-mRNA cargo, we have freedom to use the delivery system to build our own programs, and so far, that's how we've each thought about it, is to use our focus and strengths to focus on each of our own programs. Doesn't take away the opportunity to collaborate together on programs, but at the moment, it's really defined by cargo and by targets. Okay, and, you know, CAR T is an increasingly competitive space, both on the oncology side and now on the autoimmune side. So, given your delivery technology and iqDNA, where do you see the areas where Generation Bio can differentiate from the competition? Yeah. Well, let's maybe take T cells in two buckets and start with CAR T, as you just did. If we take theoretically the idea of using a short-lived cargo like messenger RNA in T cells with a selective and redosable approach, autoimmunity is really attractive there because it's increasingly apparent that short-term, deep depletion of B cells in circulation and in tissue may allow for a reset in certain autoimmune diseases that are primarily B cell driven. I think that's likely to be an application space for the delivery system with messenger RNA. I think there's a separate suite of applications in T cells, where you can modulate their behavior using other cargo to either knock down targets or more durably drive gain of function in targets using a cargo like iqDNA. So it's in this broader category of T cell immunomodulation that you're likely to hear about GBIO-specific programs. And the more we look at the T cell environment, the more convinced we are that there are no T cell restricted delivery systems available, so we've never done the experiment of what it looks like to knock down certain autoimmune targets, for example, or durably elevate certain autoimmune or autoinflammatory targets. So we think that's gonna be a very interesting space for development for us, based on this delivery system. Understood. So there is a lot of room for differentiation there. All right, so I know you said you were in non-human primates or moving into non-human primates. Is there any guidance for when we could potentially see some of the outcomes of these experiments that are being done now? Yeah. So we've said that we'd like to complete the picture on understanding the ctLNP delivery system for T cells sometime this year. And so we'll let, kind of let you know when we're able to announce that. We'd like to do that in conjunction as much as possible with some scientific or medical meetings. And then we haven't yet guided on when we'll talk specifically about indications or timelines to the clinic, but we're working very hard on being prepared for that, so stay tuned. All right. So if we could shift gears, I wanted to touch on the sickle cell disease program. Yeah. So as a first question, we—this is an area where we do have two approved products now. They are off to a bit of a slow launch. So my first question for you is, how much of this slow launch do you think is related to the method of delivery, where you do have to deliver chemo and basically do a stem cell transplant, versus just the overall size of the market? Well, I don't want to overplay my close, you know, familiarity with what's really happening on the ground in, you know, centers and reimbursement. It's very complicated because of what you said, that it essentially involves a transplant. But having interacted with both the sickle cell and the beta thal populations clinically, there are a lot of patients. This is not likely to be restricted by the patient numbers, certainly not at this stage. I think it just the reality is, it's a several months-long periodic process by which the cell collection and transduction and amplification, as well as the ablation or conditioning, it just soup to nuts, it's four to five to six months, and it's very involved. So, you know, I think this is very similar to a lot of other spaces, where you get this dramatic changing of what's possible clinically through the technology, but the first approach is not necessarily the one that can allow it to become generalized. And I think the industrial and clinical limitations of the ex vivo approach will serve to show what's possible, but it probably won't be the approach that can allow it to become a generalized, routine, you know, procedure. And that's really our ambition. We'd like to have a easily redosable point of care ability to reprogram HSCs so that the erythrocytes ultimately, you know, can have the appropriate levels of either native or fetal hemoglobin to cure the disease, but in a redosable point-of-care way that doesn't require transplantation. I think there you have the opportunity to try to get to more global access for a therapy like this. Understood. One thing I wanted to ask was, how does your approach to sickle cell compare to these approved methods where, you know, one company is expressing an anti-sickling protein and the other is increasing levels of fetal hemoglobin? Just given your platform and some of the work you've done so far on the preclinical side- Yeah ... which of those approaches potentially makes more sense for Generation Bio? Yeah. I think our view, like it is with factor VIII, is that an endogenous protein that functions in the normal physiology of the human body is preferred. So whether that's restoring normal hemoglobin function or elevating hemoglobin, fetal hemoglobin, these two approaches we know are well understood and operate even in the genetic kind of experiments that you see in patients who have polymorphisms, for example, for inducing hemoglobin F production. So that's our preferred approach, and what we haven't settled on yet is what is the right way to intervene on the genome in HSCs in vivo. The dynamics in vivo are quite different from what they are ex vivo. And so we want to keep an open mind about the payload approach for sickle. We're working with a few different systems to see what's best in vivo compared to ex vivo. Okay, and given there are approved products here, I did want to touch on, I guess, what your goals are for the program, or, maybe a better way to phrase this is: where you think the bar is for efficacy. Do you think that only an approach that can completely eliminate vaso-occlusive crises is, you know, would be viable commercially? Or, just how are you thinking about the market here, and what the range of efficacy you would potentially see or what your goal would be for that? Sure. So my experience in rare diseases is that every sort of therapeutic wave elevates the set of therapeutic expectations for clinicians and, and for patients, and ultimately for regulators. For the reason that you mentioned when you started in this sickle section, the challenge is always to elevate the bar for efficacy, but that bar for efficacy, I think, is already pretty spectacular with these ex vivo approaches. And what's difficult is the side effect profile, and the expense, and the duration of the intervention. So I would be personally very satisfied if we could hit that efficacy bar. Like for hemophilia, where we say we can hit that efficacy bar and let people live for years at a time, free of disease, here you'd want the ability to create potentially a lifetime cure, but to do it for more patients with a much lower bar for safety and ultimately also for cost. I don't. Obviously, we always think efficacy can be better, but I have to say, in this case, the efficacy bar is quite good, so I think it's there. It's about access and safety. Okay, and, before we move on to the next program, could you just tell us, I guess, where we are in clinical development here, and what the immediate next steps are for the program? Yeah. So here, we're earlier. We're going to describe where we are on delivery first, and then the next step will be to show delivery in combination with an editing system that allows us to create the changes that are needed in vivo. And we'll progress that combination from humanized mouse through to NHP, and then we'll be in a position to talk about timelines. Okay, we only have about three minutes left, and I don't think I saved enough time to talk too much in detail about Hemophilia A, but this is the first indication for the iqDNA platform, the liver-targeted platform. I wanted to ask you, why did the company choose to go into Hemophilia A as the first indication? Is there anything particularly attractive about this market or that's a good match for the technology? Yeah, I think it's a happy situation where both are true. So it's a great match for the technology because getting long-term gain-of-function with an endogenous protein, whose connection to therapeutic levels and ultimate performance in humans is probably the most direct that I'm aware of. If you know you're getting a certain level of factor VIII with the human protein, you know what it's gonna turn out to look like in humans. As it turns out, I think it's a very attractive, maybe the most attractive, rare disease market globally. It's somewhere between $12 billion and $13 billion annually. It still is only a quarter penetrated from the perspective of the global unmet need for hemophilia. For the development horizon, again, as I was saying earlier, what's important is being able to hit the efficacy target but do it for long stretches at a time. I think the challenge for traditional viral gene therapy is it's not doing either of those things. It's not hitting the efficacy target reliably or consistently in patients, and it's also not lasting, and it takes away the opportunity to dose again. I think that the competition in hemophilia is about long-acting, natural clotting factors and bispecific antibodies, neither of which so far has the opportunity to go out for years. I think there's something really nice about both the attractiveness of the market, but also the fit for the technology. That's why we chose it. All right, and where else do you think the iqDNA platform can go from here? You have your first lead indication- Yeah. just trying to think about the range of potential different- Yeah ... disease areas you can explore. yeah. iqDNA, for me, fundamentally, is a payload story. So it—what does the payload offer? Titratable, durable gain of function for large genes, and I think in the liver, that creates a franchise of protein replacement applications. So there's hemophilia, there's LSDs, there's IEMs, and as a payload, iqDNA is an amplifier for the T cell delivery system. As we were talking about earlier, there are certain immunomodulatory indications where durable gain of function can be very interesting. I think that's likely to be true in other spaces. For HSCs, I'm not so sure. You know, in HSCs, you probably need to drive insertion of a DNA template to get really durable changes. So I think the gain-of-function application iqDNA is likely to find other cell types after T cells in the liver before it finds a home in HSCs. All right, great, and it looks like we have to wrap it up there. Yeah. So, Geoff, thank you so much for the time, and look forward to seeing all the-