What I'm going to do today is go over the basics of atherosclerosis, and then talk a little bit about what we're doing at repair by our technologies to try to defeat atherosclerosis. And you need a little bit of the grasp of the basics to understand you know why what we're doing is very novel, and a big departure from the past, and also very likely to solve the problem. So you'll excuse me, teaching you some some basic stuff, those of you who already know this, and I see some of our investors already in the house. So hi, guys, this will be an additional update for this quarter. So the very, very basics, what is atherosclerosis, I mean, on the right, this is this is the traditional view of what is going on in your body, as you get older, your your arteries are gathering this gunk, which doesn't just narrow it contrary to this, this picture, narrow and weaker. So as you get older, and the gunk gets sloppier, and the arteries get more weakened, eventually either the gunk breaks up and flows somewhere in block something or the artery just ruptures. And either of those are obviously very horrible things. And the least you get away with when that happens is a severe embolism somewhere in your body. And this kills a lot of people. In fact, it's the it's the primary cause of death in our species, and a number of other mammalian species. As a topic, this makes it very important. But how bad really, and how bad really is if you follow the World Health Organization, sort of category of how humans die. atherosclerosis is the cause of one and two, both of the 27% of everybody, this is actually an arguable number. Some people like to think that it's more like 44%. And we can debate that other that other 20% also, but this is a terrible problem, it's a quarter of everybody, we should be doing an immense remor amount of stuff to try to deal with this problem than we are. But what is the real what really is the cause of atherosclerosis and one has to ask this because I know that everybody has this vague idea that it's it's cholesterol. And we'll we'll get to why that is. But it's not really cholesterol. Its macrophages, say your macrophage cells in tissue are derived in part from, from the monocytes that flow around your bloodstream looking for problems. And when they find a problem, which is that the the wall of your blood vessel is unhappy for various reasons, they dive in, and they try to fix things. And the thing that they're trying to fix here is that you have a bunch of gunk sitting in your sitting in your blood vessel wall that needs to be ingested and thrown back into the bloodstream. So it can go back to the liver. And unfortunately, as you grow older, macrophages become increasingly incapable of dealing with this problem. And what you get is on the right is macrophages to become foam cells, because they're completely overwhelmed by cholesterol because they've stopped being able to process it properly. And then from there, it just gets worse and worse and more pathological and the smooth muscle gets involved. And basically, you get into the the block situation, as shown in the, the yellow here. But the root of this is the macrophages. When you're young macrophages work just fine. Your blood vessels are not covered in block when you roll they are and that is entirely down to the macrophages that just just not being able to do their jobs anymore. So why do the macrophages stop being able to do their jobs. In order to understand that one has to look a little bit about cholesterol, cholesterol transport in the body. And the first thing to recognize about cholesterol is that it really isn't created or destroyed. All that much, it's suddenly excreted and ingested. But cells don't break down or convert or get rid of the cholesterol they don't want locally. they hand it off. They take it up when they need it, they don't manufacture it, and they hand it off to other other cells and other parts of the system when they no longer need it. Because cholesterol is expensive to create. So for the first of to a first approximation setting aside the central nervous system, which does its own thing. Cholesterol is created in the liver. It gets stuck onto LDL particles, low density lipoproteins, it goes into the bloodstream, it gets stuck in a blood vessel wall, the macrophages eat it and then throw it back into the bloodstream to attach it to HDL particles that can flow back to the liver. And you know LDL particles and HDL particles do much the same thing when you're young and old. It's the macrophages the proper they they stopped doing their job.
So why exactly the macrophages stopped doing their job. There are a variety of issues. Firstly, systemic inflammation, a macrophage cell is an innate immune cell and it does respond to the inflammatory state of the environment. When you're older you have systemic inflammation throughout your body. And therefore more macrophages are going to become immune to listen to that and become m one macrophages which are out there hunting down pathogens and generally being aggressive and contributing even more to the inflammatory state. Where he wants in your in your blood vessel walls are m two macrophages that actually dampen inflammation, and do the reverse cholesterol transport where they suck in the gunk that's in your artery walls and throw it back into the bloodstream. But the more inflamed you are, the less of that is going on. Secondly, oxidative stress, which is the presence of too many oxidizing molecules in your system, this is a result of both inflammation and mitochondrial dysfunction. Whereby your your mitochondria are generating a bunch of reactive molecules and cells are generating generally reactive molecules and it goes hand in hand with inflammation to a certain degree, what happens is cholesterols become altered, and the LDL particles that carry them become oxidized. And these things are toxic to macrophages, they hate them. So you got a selection effect where your blocks are gradually becoming more and more toxic to macrophages. And it just gets it just kills the macrophages that come in. Lastly, too much cholesterol, which is probably the least important in normal, normal people, extremely overweight people and people with very high levels of cholesterol for genetic redo to genetic conditions, if there's a level at which just too much cholesterol overwhelms your macrophage. And if you go back to here, this mentions oxidized LDL was macrophages love it, they want to eat as much fat as they can. The more oxidized LDL you have, the more likely it is the macrophages are going to become totally overwhelmed by the cholesterol, it's in the environment without having to have an overall high level of cholesterol. So what this leads to is you get a feedback loop, which causes plaques to grow. A plaque is an inflammatory, horrible, toxic environment, the macrophage comes in there, it becomes a foam cell, it says help help send more macrophages that it dies. So you have this positive feedback loop of growth, which is based on killing macrophages, your plots are a macrophage graveyard, that's really what most of it is dead macrophages. That is that is the underlying problem that causes atherosclerosis. Now as I'm sure you're aware, there's an entire research community and enormous pharmaceutical concerns and whatnot focused on purely lowering LDL cholesterol, only just just taking that part of cholesterol transport from the liver out to the rest of your body and turning it down. Less LDL, less LDL cholesterol. Now this probably helps a little in the sense that you're reducing oxidized LDL you're reducing altered cholesterol is ending up in the in the blocks and your lower giving giving your macrophages a little bit more breathing room. But frankly, it doesn't work enough. we've demonstrated we the research community have demonstrated that if you if you really really aggressively lower LDL cholesterol to 10% of human normal, you're still not going to stop people dying, you can't get the plaques to reverse the existing plaques are still sitting there being macrophage graveyards, and calling in new macrophages taking away the input of cholesterol at that point doesn't help. So there's a whole bunch of fascinating stuff that's going on in this LDL lowering industry and continues to go on. A lot of it is presently based on mutants who over a lifetime have have a dramatically lower risk of cardiovascular disease, which is great. I mean, if you have low LDL cholesterol, like really, really low LDL cholesterol over an entire lifetime, like 80 years, you're going to have half of the risk of dying of cardiovascular disease. But if you're trying to make a therapy out of that, and you're giving it to someone for two months, this really doesn't work very well. It's just just not as good. And they really don't do more than starting this do the old standard of drugs that lower LDL cholesterol small molecule stuff. So as a result of this huge focus on decades of controlling LDL cholesterol reflexively to the point where a physician will just not even engage brain and prescribe statues. As soon as somebody turns up over the age of 60 and or with even slightly raised LDL cholesterol. It's still the case that atherosclerosis kills At 27% of every way.
And the drugs that we use, only achieve attended 20% mortality reduction, and there's definitely a heretic community in the research field who will debate that 10 to 20% number and say that that's probably not true, because any number of trials have been conducted in which they did not achieve that level of mortality reduction in humans.
I see. Yeah. And that heritage community, which I wanted to ask you about some, arguably, adjacent to them, um, they would also bring up that there are downsides to status so that even if there's a reduction in atherosclerosis, there's not a 10% reduction in overall mortality or quality of life.
The side effect of pytor, statins are really, really bad. For a large number of patients, you and you know, even moderate dose statins, you have a percentage of the patient population, that's probably under 20%. I'm not sure what the number actually is, but it's about there who just can't use that ends, because they just they just isn't good for them. Further, whatever you do with blood cholesterol, if you have lipid Laden, soft Clark, they just really aren't many good options. Getting rid of those blocks just isn't isn't on the table, there really isn't much you can do. So we need a better way of going forward. And yet, and yet, if you look at like, you know, what is the one of the latest $3 billion companies that are out there just going public, what are they doing? They're lowering LDL cholesterol, if you look at like the latest therapies where they're planning to charge half a million dollars a year. For these for these high tech therapies, what are those therapies doing? They're finding new ways to lower LDL cholesterol, it's not a good environment. What are the alternatives? So let's start with the ones that don't work. As you as you might recall, I mentioned you know, inflammation is a big problem here. But if you reduce inflammation, systemically using the approaches that are available now, studies suggest that you get about the same benefit as you do from lowering LDL cholesterol, which isn't to say that somebody couldn't come up with a way of doing this better. And in a more targeted fashion, that actually works. For some definition of works. But the tools that are available to reduce systemic inflammation are just not, they're pretty blunt right now. And they just don't do enough. I think there was a study I was looking at recently, which shorts showed an 8% sort of reversal a plot which just isn't, isn't good enough. So alternative number two, which seems much more much better, you know, as soon as your as soon as you'd go to your ceiling are much better as mice. So reverse cholesterol transport is the part where your macrophage sucks up the cholesterol hands it off to the bloodstream. And there's a number of genes are involved in this, this this sort of block diagram here. These if we imagine these blue things are macrophages, what they're doing is they use abca. One to handoff to an HDL particle initially, and then ABC, g one helps you add more cholesterol to the particle, the particle heads back to the level where it's picked up. Next threaded into, into and you know, objective from the body. This way, anything you do pretty much anything you do in mice to make one part of this system or more parts of the system work better, you can upregulate abca, one, you can put more HDL particles, you can make macrophages consume more cholesterol, it all works great in mice even use, some of the methods have achieved 50% reversal plock limits, which is amazing. And should cars correspond to roughly a 50% reduction in mortality. But every time they tried to do something in humans, they fail. There's a whole list of clinical trials that have failed over the last 20 years trying to improve the various cholesterol transport or things that work really well in mice. So what that tells us is that we do not understand something very important about the way in which cholesterol transport is rate limited in its different steps in humans versus in mice. So anybody trying to do something here, I wish them luck. But the odds are not good based on based on historical, historical efforts. So my position our position at repair is the position of a number of other people is that the true path forward is stopped macrophages, exploding the world, make them resilient to the environment they find them in, in all tissues. So if they can just be made to not do the crazy things they do when they're exposed to you know, oxidized cholesterol and LDL particles and and systemic inflammation, then great. In theory, if they can keep doing what they did when they were useful, they will just dismantle clock over time. And atherosclerosis were worse because that's what these cells are meant to do. And it's what they do do if they're not being if they're not being trampled by by the circuit. stances of being old.
So there's been a number of people trying this, some of it hasn't made it very far. Some of it's quite interesting. And sometimes there's an overlap between those two, there was a recent paper in which the hypothesis of the effect they showed is that if you target lysosomes, in macrophages, with antioxidants, it prevents the oxidized LDL particles from messing things up. And therefore, these more cells, more macrophages are doing their job. And this has been shown to reverse block by 50%. In a mouse model, it's entirely possible their hypothesis is wrong. And that delivering the antioxidants is improving something else in the picture. But it's certainly something that self experiment is should pay attention to because these antioxidants are easily available. Secondly, there's the underdog pharmaceuticals approach, which is to sequester seven keto cholesterol, which is a highly toxic altered cholesterol, which which is thought to be important in, in atherosclerosis, but the only real way to test that is to feed the drugs to humans, unfortunately, because mice just don't mice just on, on big on having enough seven keto cholesterol to make a difference here. So we'll see how they do, I hope it works. And lastly, there's our approach, which is to genetically engineer macrophages to give them the ability to degrade in situ, any excess cholesterol they encounter, whether or not it's older. So I'm going to talk about that a little because obviously, that's what I know the most about. It's a, it's a really interesting, it's a really interesting approach. So if you remember one thing about the company name, here, it's repair. If you want to address something in aging, you better be better be repairing something, if you can't point to something, that you're actually repairing a form of damage, a form of dysfunction, and you can clearly say I am fixing this, then you might not be doing the right thing. So obviously, we're currently working with an investment bank to do a clinical raise. And that requires me to show you things like this, which I'm sure you've seen before, the future is hard to predict, we're not trying to In summary, what we're doing is taking a stepwise approach to it take this approach of allowing macrophages to select grade cholesterol and stepwise approaching the barriers atherosclerosis conditions, in order of patient number of patients. So you start off attacking an orphan condition, homozygous familial hypercholesterolemia, then you go into the larger, the larger patient groups as you gain experience in doing this, and unlike most therapies, we can actually apply ourselves to any form of atherosclerosis, whether or not it's genetic, we don't care how you got the blocks, we just break them down. So what we're approaching as our lead therapy, we've also we've done a V, we've demonstrated the AV delivery of our cholesterol degrading protein has a very large effect 48% in a month, which is really big in the scheme of things in comparison to other other approaches. But our goal is to produce a universal macrophage cell therapy. And I'll explain a little bit about that we can skip over the
are you in the right slide? Which slide you're going to be on
at the moment. I'm heading here.
Can you see what is here?
Slide five, atherosclerosis is caused by
know we on slide 13.
Really? Wow, that's really interesting. You'll still back on the old the old document. Let me reshare. Fun. I learned something about how sharing works in Linux today.
Can you now see? Yes. Great. Excellent. Okay. Let's Let's we can talk about I won't go over that. Again. Let's Let's start with the but that afterwards Groasis is, is as I said, it's this is the simplified view. atherosclerosis is basically the encounter of an aged macrophage with cholesterol, at which point, you get a lot of cell death and cholesterol based plock. Primarily because normal macrophages can't do anything with excess cholesterol if you overwhelm their existing systems for trying to get rid of it. by handing it off to HDL particles, you're done, you get a foam cell, if there's no way for it to inherently deal with this degree of cholesterol. And with this picture in mind, the whole spectrum of LDL cholesterol lowering drugs and that sort of a list right there really only lowers the input to the problem. And they can't lower it infinitely because the macrophage is in the block. It's not in The blood stream, and the clock is packed full of cholesterol and toxic, horrible nastiness. So you're not really getting a great deal of boost out of out of lowering the input from the bloodstream, your problem is that the plaque is sitting there. And you can't reverse it. By doing this LDL cholesterol lowering business, you still have macrophages exposed excess cholesterol and becoming horrible foam cells and dying. And the horrible foam cell dying leading to your clock
gives you this this
point that has to be made to a lot of people unfortunately, which is your risk of death is not due to LDL cholesterol is due to how much block you it's exactly how much block you have. And how much high risk block which with a soft block, which determines your your your mortality. LDL cholesterol, while it's been widely accepted as a surrogate marker now is just irrelevant. It's not It's not the cause of your death. And that's why different people can have different levels of cholesterol in the blood stream and have white divergent mortality risks is because of the block that Stadio macrophages, not the LDL cholesterol. And the fact that it is the plugs is why we have this list of drugs, starting with the ultra cheap and heading up to the ultra expensive, which frankly, are probably not much better than the PCs kainai inhibitors. Because lowering cholesterol can do exactly this, it can reduce your mortality by probably 20%. at most. It doesn't matter how much you pay big pharma, it's still going to be 20%, at most, because the mechanism is exactly the same. And it has exactly the effect it has on on your macrophage shelf. So the point of the exercise is, what should we do differently. And what we should do differently is make macrophages invulnerable to the block based environment as best we can. And our idea of as best you can, is you give a macrophage the capability to break down cholesterol safely locally. And I should say that this is not a trivial thing to do. Because a cell is basically, you know, an enormous lump of cholesterol, that it uses cholesterol everywhere in the cell membrane. The reason why we never evolved to break down cholesterol when it's harming us is that cells on are they have cholesterol everywhere they use it for for membranes. So you couldn't evolve something that just randomly went out there and just chewed up cholesterol away did what he saw it. And that's why delivering things like cyclodextrins as underdogs working on is not quite simple either. Because you know, the first thing that will happen if you dump a bunch of cyclodextrins into somebody is that blood turns to mush, whereas it will consume all your blood cells, alcohol or cholesterol or their wolves. The underdog has a way around that. But it's still you know, they have to be careful about what they're doing. So the the objective here is a safe way of breaking down cholesterol. It but only the excess cholesterol, which is what we achieve are the specific mechanisms we we put into these cells. Now, we can demonstrate that we can put these mechanisms into any old cell. And the output is exactly the same. We get a metabolite that is safe and more soluble and leaves the cell and is broken down in the bloodstream and got rid off very quickly. It doesn't matter what cell we put it into 293 T's our workhorse cells researchers use united three sevens are human macrophage and immortalized line you get exactly the same output. And in fact, for any other type of cell we care to do this with. It's a technology that can be applied pretty much anywhere. Now, what this means is that we can take macrophages and raw to 60 fours are a mouse line and immortalized merece line and macrophage like cells. And we can give them the ability to express our CDP proteins. And what happens is that you dump cholesterol on them, the unmodified ones become very unhappy. And the green there is is basically foam cell behavior, whether they're sticking this cholesterol inside them and becoming pathogenic and inflammatory and I'm happy on the right, very little of that. The CDP cells just eat the cholesterol and get rid of it. And that's exactly what we want because these cells are competent, the ones on the left not competent. What you want is competent macrophages in your plot. So our proof of concept with AB we delivered a very high dose of AV to two mice, atherosclerotic mice and you can see the difference left to right between the controls and the treated red is basically plot lipid laden block. And these are cross sections of the aortic root the little fiddly bits in the middle of valves We got something like a 50% reduction in a month following a single treatment. This is a very powerful effect, we have quite a sizable impact on the way this functions. So going forward what we're doing right now actually, we're injecting mice, we've been injecting mice with the cells of the last month we hope to have some data by the end of the year.
We we take IPS C's, from mice or humans, we have partners that we work with who provide us with, with well characterized human lines, the lines are, are disrupted in a certain way to make them universal, you get rid of the markers on the surface that would make them recognized as foreign. So you can introduce these cells. And if you look at things such as what sauna has been doing recently, they've delivered universal IPS C's into non human primates and shown they produce no meaningful immune reaction. This is a very important technology because it means you can often make off the shelf cells you can get one line of universal macrophages to we differentiate ourselves from these universal cells and which Express CDP and this is the way you produce a cost effective cell therapy that will be the same level of expenses, today's you know, first generation stem cell therapies that are derived from very prevalent sources. And then what we do with this is we stepwise go deal with the orphan indication of homozygous familial hypercholesterolemia, which has very few patients and the FDA will give you a much easier time of it, because it's, it's an orphan indication, then you go to the one where you have a million patients who have heterozygous familial hypercholesterolemia, which is the they have one of the genes in their chromosomes mutated, not both, these guys almost have a worst time of it, in the sense that they're often discovered late. And when they discovered late, they have very heavy plock dangerous clock, and their life expectancy is just not great. I mean, these guys, obviously not good at all to have a life expectancy of 33 years. But these guys are the sort of people who suddenly die in their 50s or late 40s. And then later, we want to take this to and by this point, we're talking about an industry not just a company, want to take it to high risk subpopulations of atherosclerosis, people who have detected in scans, high risk flock that will kill them. And ultimately, we think that you could take you can take, you know, the bite, the largest lion's share of that 27%. And you can use technologies such as ours, to completely remove that cause of death from humanity. How long that's gonna take who knows, but that first most highest risk population and be identified via scanning technologies. That's where we start. So our pipeline, you know, I just told you looks much like this, the market size is increasingly enormous. And this 22 billion is probably an underestimate. I'll skip over our IP, who we are, so you know, me. You guys have yet to meet more ad, or hit worth conferences not being in session for the last, you know, the last 18 months. But as soon as conferences are up and around again, you guys will have chance to be more ad our Chief Scientific Officer, he's a good friend of the inventor of technology. I'm very familiar with the atherosclerosis space. You will know Bill, of course, and Bobby Kahn is an atherosclerosis focused physician who acts as our chief medical officer has taken drugs through the FDA, which is an essential experience. We have a great scientific advisory board. Richard honkanen invented this technology. I think many of you know Graham, a feature of our our community, if you're dealing with macrophages, you need to have immunology expertise, they're their own little cells to work with. And of course, we keep people around to keep us advised on our on cardiovascular of never physiology, for all the obvious reasons. So as I mentioned, we're raising aggressively. Right now, we are working with an investment bank to get a $20 million round together to fund our past two to ind for homozygous familial hypercholesterolemia. I should say that as this is going on, we're very happy to raise from from angels via safe note in order to extend our runway. And I know that those of you here who are already investors, we've already talked to you about that. Those of you who aren't our investors at this entry as you by all means, reach out to me. We're online repair biotechnologies, just send us a message and we're happy to talk. So that in a nutshell, is that and the one last thing I should probably say is that if you want to look for a comparison to us ish birth therapeutics, who are only dealing with familial hypercholesterolemia, and only lowering LDL cholesterol and yet have evaluation $3 billion. We think we're a lot better
than they are. And with that,
thank you guys. I'll take questions.
Fantastic. Thank you so much reason. Okay, this is brilliant, I will stop sharing your screen just for now. But you know, feel free to make it pop up anytime and when it's useful. We have the first question from Robbie. And then we'll have one coming up which are without. And this is just to say if you want to ask a question to pose it in the chat or even raise your hand, and we'll get to you. Okay, thank you. Ravi, first.
Yeah, thanks. So, what have you mentioned briefly banana questionable. cyclodextrin is that compared with what you were looking at, and
you mentioned a little bit that it was perhaps the indiscriminate, normal cyclodextrins bind cholesterol and are indiscriminate, which is why they had that that dose limiting toxicity is that initially, you lose the hair cells in your ear, because for whatever reason, they're very sensitive to having the cholesterol hooked out of their membranes. And the next thing that happens to you keep increasing the dose is that your blood turns to mush. So nobody really looked much after what happens at that point. But the the underdog team have, I believe, engineered this cyclodextrin to preferentially bind only seven keto cholesterol which should greatly reduce its its toxicity and allow them to dose at levels where you can get rid of a significant amount of, of seven keto cholesterol, at which point that's a great test of how important is seven keto cholesterol to atherosclerosis? if that answered the question. Yeah, thank you. Okay. And I think Mike had asked, Are there reasons we'll find this to everyone? It's a cost is a cost question. Actually, if you look at the cost of cell therapy, once you crushed it down using a universal cell line, you're looking at, you know, something under $10,000, I would imagine, and cell therapies at the moment, and the first generation stem cell therapies, those things are a few $1,000, if you get a good provider, and they're in that range, a few 1000 to 10,000. And the first thing that any VC will tell you is You're crazy. If you think you're going to treat 100,000 people with something that costs $10,000, this isn't gonna happen. They don't want to hear that. So you really need to take that sort of therapy and apply it to the highest risk patient groups first. And that needs to be your plan. Now later on in the science world of the 2030s. Once we've had 20 years of having a selfie that everybody wants to use, maybe we can crush it down to the point at which you can treat everybody I would certainly hope so.
Lovely with Korean, then look, and then Caliban.
Oh, hi. Yeah, thanks. Um, so Gosh, I would love to have an hour's or two worth of conversation with you, because I've studied this topic a lot. But I'm going to just ask for starters, one thing, which is where do you come down on the role of coronary artery calcium and the possibility of regressing it?
Right, I think that's that's, funnily that's a totally separate topic. I feel there was a, there was a really good paper recently that that reviewed the the biomarker relevance of coronary artery calcification testing, versus she'll be actually be looking at Clark, they found a great correlation. But these are really two separate processes. I mean, obviously, there's interaction in the underlying cause of them. If one believes that calcification is an inflammation related topic, largely, certainly there's good evidence for senescent cells to be important in calcification. But this is sort of a it's a thing that happens in parallel with with whatever else is going on with the formation of atherosclerotic Clark, they're two separate, two separate things that end up making each other worse, in the sense of are you more likely to have a catastrophic outcome as a result of either of these? Yes, because they're both going at the same time. But I think they, they need to be dealt with in very in quite separate ways. Because they're, they're very separate from problems unless you're really looking at the root root causes such as inflammation. That was a way to stop all older people having rise in oxidative stress and rise in inflammation, maybe you'd have a whole lot less of both, but for entirely different reasons.
May I ask a follow up Elson? Go Okay, thanks. Um, I'm okay. I thought that calcium was like the end phase and like plaque is a there's a whole cascade process from a wounded artery to plaque to There's some things you just do, you know, macrophages plaque, and then calcification is the end state. Am I wrong about
that? It's not that that happens in block because blocks are hugely inflammatory. So whatever calcification processes exist, you're going to get more of them in that vicinity. But you also get calcification without clock. It's all good. If you go get it if you're over age 50 and go get a scan of your lower body you're probably gonna see clock in your, in your legs. Not clock sorry, calcification.
Oh, really? Okay. Well that's, I mean, you're mostly talking about ch D. Are you know, are you talking about cardio? Are you talking about circulatory disease in general?
Or in general like how much calcification is going on in your arteries?
Not good i mean it's it's your product and your company oriented towards coronary artery disease or general circulatory disease
Oh everything we were introducing macrophages so you know, they go everywhere. So we're interested in the effects No, I mean, obviously, you measure the outcome in, in coronary arteries because this way you can measure the outcome. You but you expect you expect atherosclerosis to have a meaningful effect in terms of small vessels as well and certainly what it's hard to tell what's going on in there we expect the macrophages to be heading off there to do their job as well. Okay, great, Luke. Hi,
I'm it's two parts one is technology one was more about the business so is it something where you need to have a therapy regularly to remove the plaques or once the cells introduced? Do they just live inside you for the rest of your life and continue cleaning up your plaques? And then of course if question on that is if it's if you do have to keep doing it if they do live inside you for that long Are there any risks of since you have something that is genetically modified problems that are very very long term? A second part is how did you start the company how did how did you get the idea how did you meet the people? And then what are the long term goals of it?
Well the second part you can blame Aubrey de Grey for that as you can blame him for a lot of things he actually
says in reflecting on that as you've been speaking Yes.
I he introduced us to Richard Hong cannon and knowing that I'd been very interested in this this part of the field for a while and it kind of went from there because it was obviously too great not to do and we said we said to the university folk give us a great deal and we'll prove that this works in mice or doesn't work as case may be and that's what we did so the first part
the the methods in order to add a song to distract the people are you rich was at the university alright he's still there. He works at the site and continuing to do and and was here originally doing this work or were you convinced him to do the work like he was Yeah,
he originally did this work he found here it's actually not his wheelhouse. His wheelhouse is molecular biology of certain aspects of self behavior. And that led him to oh wait we can use this to cure atherosclerosis and hence he can do it came and presented at undoing aging A while back and from there it was sort of inevitable that I would end up talking to him and then he goes the first the first part of your your question macrophages have a lifespan few months. So if you if you put monocytes into into the bloodstream when they go to Clarks you're looking at a treatment it's going to last for a few months. The question of how often do you have to do it is a you know that's a that's a biodistribution dose response type of evaluation that we are we couldn't tell you. What we would like to have the outcome be is that you take this therapy at most once every few years. While scans show that you are you are in need of it. We don't intend to replace the x the presence of LDL lowering drugs for those people who can take them. And certainly that would be a hard job because they're very entrenched. But there's an awful lot the remaining 80% of excess mortality due to cardiovascular disease that is there to be dealt with. And that's what we will. That's what we will do. And what's your long term goal with the company? The long term goal here well as I'm sure many of you know, I have a million things I'd love to do. I would love to take this company public on the strength of this and from there have it become an umbrella A company that does many other things, whether or not that whether or not that is the fate of repair. Who knows, but I would very much like to, to pick up our program on the famous again and do many other things. Once we've, once we've proven that we can do this, we have access to public funds in the public markets there, there are a lot of other things we can take up and move along. Thank you. Okay. Okay,
we have Caliban. Next. And if you hear again, read out your question as well. Okay, you are here, you want to ask him to do on unmute yourself and ask him otherwise, I'll do it,
I think I found your T two one. And on m two dichotomy, would we maintain that the the m one m two dichotomy is useful. So macrophages, like all cells are state machines, and they live on a they live in a state space. So when people say, Well, your macrophages are m one or their m two, where m one is inflammatory, and horrible and useful pathogens, and m two is anti inflammatory and reparative. In the sense that it participates in tissue maintenance more, this is sort of obviously this is this is slicing your very complicated state space into a big buckets and saying, yep, this thing's in the bucket, or it's not a switch, it's not like you know, it's it's a where you are in a complicated space of tendencies, or you're expressing some things more than other things. But I think it's useful because you can clearly go take a bunch of macrophages and stick them into a flow cytometer and stain for, you know, unstained for various surface markers, and you will get quite clear distributions that are sort of m one, and m two ish. And of course, you know, 10, maybe 10% of them are off doing something weird, that's m one, or m two, or even something completely different, again, zero. I think it's useful in the sense that there are ways to push macrophages in one way or another. And you're really dealing with aggregates, you're not, if you have an individual cell, good luck. That was not a research project you should have undertaken. You should be thinking more about aggregates of macrophages and what the aggregate behavior is. And that's really the best you can do. But it is a useful, it's a useful more
new way of Cosmo and then Korea.
Well, I have one question, but now I've got two questions. Since you're talking about macrophage polarization. It just so happens that macrophages are from the same lineage cells in the bone that through polarization states regulate the deposition of calcium. Is there any evidence that that is the same mechanism by which calcium is being deposited in the arterial plaques?
I don't recall, I thought that was more of a smooth muscle problem. We only go convincing smooth muscle cells to start behaving like bone cells through inflammatory signaling, or at least that's my recollection of the literature. I've read on that topic.
Gotcha. Second question briefly, do we? Do we know what the precise mechanism by which oxidized LDL causes them to die? And is this related to cholesterol crystals?
Yeah, we actually that that's a that's a good one. And if you go read the average review paper on LDL cholesterol, it will not offer an opinion on that. So I think the I think that's very much up for up for grabs the that antioxidant paper that I mentioned, in which they target antioxidants, the license zone, and sea effects is and and you're obviously they take a bunch of, of cells, in addition, shove oxidize, you know, shove oxidized LDL particles into them, and show that they go to the lysosomes. And the cells become dysfunctional. So something something lysosomes overwhelmed, you know, that that's, that's well known to be a problem in aging in general, in long lived cells, whether it's some version of that is happening in, in macrophages. Yeah, who knows? Our our take is that, that may not be as important as the fact that you have these oxidized LDL particles being taken up aggressively through scavenger receptors by macrophages. So it's not necessarily the LDL. That's it's the oxidized LDL particles themselves. It may just be a matter that now you're dragging in more cholesterol than you can handle.
That scavenger receptor that you mentioned is the same gene in bone that regulates calcium deposition. It's something that I've been trying to figure out for a while now. We should talk.
Right? evolution loves reuse. Yes. Oh, Any more questions?
Yeah, I've got one um, thanks again. Um, okay, I don't mean to be killing the theoretical here, but I thought that the leaks for coronary heart disease. HD l to total cholesterol and HDL, LDL and HDL Try glyceride is a much better predictor of disease than just LDL levels. Now ox LDL is another thing that's obviously good that you have to care about that.
I'm not really, I think, like the evidence suggests that doing things with HDL doesn't work in humans. It doesn't, it doesn't help the problem. Okay? We should distinguish between Okay, what happens over your lifetime in response to your ratio between LDL and HDL, because basically over a lifetime, you're adding up this sort of, you know, what's, what's the balance of your cholesterol transport in the body. And in theory, more HDL is going to be good. And in practice, it looks like more HDL is, is good. But that's not the same as what can you do for therapy, where you're operating in a fairly short timeframe. And in that case, I think the clinical trials of the last, like, you know, 20 years have really shut the door on, let's put more HDL in there and humans, it doesn't work. And in terms of and in terms of lowering LDL cholesterol, great, you get the aforementioned 20% at best mortality reduction. And clearly, that's not the solution to the problem either. Once you have clocks, they will kill you. They will continue growing, it doesn't matter what you do to HDL and LDL.
But last question here, um, for me, I was a little unclear on your position on system addict inflammation, it seems like sometimes you say inflammation is the thing which is driving the trouble. On the other hand, I thought it was a slide where you were like, well, it reducing inflammation has failed.
Both it's it's a, it's clearly a contribution, because you can look at humans, again, for distinguishing the overtime versus how do you fix the problem to separate two totally separate considerations over time, more inflammation, clearly, you are going to die sooner of atherosclerosis, you know, over over years and decades. The the if you're trying to fix the problem and reverse block reducing inflammation just doesn't seem to help that much. Because you're again, the problem is that the clock is sitting there being being inflamed and, and full of garbage and toxic, and macrophages just can't deal with it. It doesn't I see. So
there's a lot of things. There's a lot of things people can do with like lifestyle interventions and drugs to stop or slow the progress of the disease. But in terms of reversing the disease, with a short term intervention, that's what you're looking at. And that's a whole nother kettle of fish.
That's a whole different kettle of fish. And it's really my opinion is the whole community diving in on these human mutants who have low cardiovascular disease, that that's that that's just never going to work. It's a huge red herring a waste of time. And the only thing we're going to get out of that is more LDL, lowering drugs that have the distinguishing feature of being vastly more expensive than previous LDL lowering drugs. And I should say those two things are actually a virtue in some circles, because it's easier to make profits off that. We have one more question here, which was why not shut down the mechanism driving macrophage invasion of cardiovascular tissue? And, you know, if if you do that, then you're never getting rid of those blocks, because nobody else is going to. In theory, we could give every cell the ability to degrade cholesterol and, and shut down the macrophage invasion. But why do that if you're already making the macrophages good?
Isn't that also a problem in the sense that some of these processes, which turn into chronic disease progression, are actually useful in a healthy person? in acute cases of like infection or injury? And so you don't
want to shout them out? Yes, exactly. Which is another reason to favor the sort of thing that we're doing, which is an enhancement, which does not otherwise change the way things work, other than just letting them work. Great talk, thanks.
Okay. Just checking that Cosmo is your question answered? Oh, do you want to ask them to listen? I assume I take this as as good. If not, then please let me know. But we didn't. I cannot wait. There's another one in the chat. We are going to therapy.
Oh, in principle? I think so. With the not with the caveat that gene therapies are really hard to target properly. Not just not just from the point of view of how are you connecting it to only express in the cells that you want it to express it in, but also how do you get it to where those cells are macrophages are just everywhere. You really want to get the macrophages that are in plock which means you need to target blood vessel walls, but then you also have the other 50% of macrophages that are sitting in your room, sitting in your spleen that you probably want to get. You could take the approach of targeting hematopoietic stem cells. And in the in the, in the case that nobody would ever want to do, you could do a matter poetic stem cell transplant, such that, you know, you get genetically engineered immune cells and in those immune cells, only macrophages express the genes of interest. But of course, nobody's ever going to go for that. And certainly the FDA would say, we would love for you if you tried to propose treating atherosclerosis in this day and age by by giving people hematopoetic stem cell transplants? I don't think that's going to. So in principle, yes. In practice, probably not a viable approach.
You're getting a thumbs up and Kosmos back.
Yeah, reason you you inspired an idea that I've just never considered before. We know that the oxidized LDL goes to the lysosomes. But I'm wondering does it go to the lysosomes? membrane?
That's a good question. I'm really not very familiar with the precise details of that I was reading up on that most recently. In connection with the with with that paper that was very recently published as I as I said, our our take on that is more that it's, it's more to do likely more to do since we get great results is likely more to do with the oxldl being an additional source of cholesterol coming into the cell over and above what it will pick up normally. So your your overwhelming the cell's ability to deal with the cholesterol is intaking. Because the oxldl is using a different set of receptors and gets taken up quite aggressively. And this is probably a consequence of oxidized LDL, actually binding to a receptor that isn't, isn't for and quote unquote, that is actually evolved for some other purpose. But we'll see. I mean, it's an interesting question. There's definitely more work to be done on. on that. Yeah. Why oxidized LDL is bad?
I don't I don't know anything about lysosomal membranes, but I just, I just plopped a photo of one in the Oh, I gave it to Allison privately, whoops, let me replaced it. Yeah, I'm seeing your scavenger receptor right in there. I wonder if it's not clogging the inside of the lysosome as much as it's clogging a receptor on the outside of the lysosomes?
I mean, that's also possible. We know the vices mo receptors are important for autophagy and other other aspects of cell function.
Yeah.
Excellent talk as always,
okay. If no one sees no reason, you're not allowed to go yet? I have one more question. And which we tried to open every one of these meetings, I hope it will be fun, which is, what could this group collectively do to further you and your work? I know that you've talked a little bit about that we pair I think, is actively seeking investors. But could you be raised two sided, like you know, of anyone super inspired by your work? What did they do to help you and your work flourish?
Um, well, I think go do well, aside from throwing us vast amounts of money, which obviously should go without saying, the, I think the best, the most interesting things that you could do, ar are in the realm of self experimentation. With respect to what can one do with atherosclerosis, and there's very little that one can do at the moment. But there there are some interesting approaches, one can take, such as trying to get some idea as to the natto kinase situation. As I'm sure you're aware, that was a Chinese study that showed sort of 36% reversal of lesions after natto kinase use for half a year. And then somebody else published a three year study in the US saying no, it doesn't happen at all. The US study used a third of the dose of the Chinese study. So at the end of the day, you're not throwing up your hands and saying somebody needs to do another study. So you know, self experimenters can do this stuff. It's pretty simple. Along those lines, I think there's I think there's a lot that can be done in order to help expand our knowledge around potential potential therapies that are not quite yet baked in terms of clinical trials and where we're really not going to see a lot more data anytime soon from the establishment.
And for we pay a bio Can people contact you via the website? Or do you want to share your email here? What's best if this goes on YouTube? Maybe also make that useful for those that are not
absolutely i mean, reason app repair biotechnologies.com if you're interested in investing or just have questions about what we're doing, feel free to send me an email.
Great microscopes were one minute, one minute under time, that's fantastic. Well that I could take this one minute to offer them just really really thank you for a fantastic presentation. I think you've you know, really given a few people ideas, and I think it's really hard to give Cosmo ideas that he has not had yet so I take that as a as a pretty Yeah, as a as a pretty big as success. So thanks a lot for your time. Thank you everyone for joining. I will be in touch with more info and that just another reminder that if you're interested in applying to foster fellowship for 2022 Cosmo, by the way, was the first fellow one of our early first cohort, I think. So anyway, and we have a great a great cohort as you can tell. And yeah, I look forward to your applications and I look forward to seeing all of you very soon again, thank you so so much reason for her for this fantastic presentation.
