These days, we are much more focused on cardiovascular disease. The thymus is an area of interest for me and something I will be returning to and Repair may return to in the future, but for now, the focus is the thing that kills the most people.
If you take anything away from what I’m going to say today, it should be the name of the company, Repair. If we’re trying to address aging, if you have a way to address aging, if you cannot point to something that you are repairing in our physiology or biochemistry, then you might not be on the right course.
We develop the Cholesterol Degrading Platform, which is pretty much what it says on the can. These days, we’re raising via our investment banks, you’ll have to excuse the expansion of our boilerplate; somebody will always complain if we don’t say, “Hey, the future is uncertain.” Prediction is hard, particularly when you’re talking about the future.
To summarize who we are, and I know many of you know us, but for those who don’t, we develop the Cholesterol Degrading Platform, this is a first-in-class therapeutic approach. Nobody else is doing this, nobody else has done this. Our primary focus in terms of applying this to the biochemistry of mammals is to reverse atherosclerosis, which kills an enormous number of people.
Atherosclerosis, unlike many conditions, is, in fact, universal. If nothing else stops you first, atherosclerosis will kill everybody. What we do is we provide cells with a de novo pathway that allows them to safely degrade or eliminate excess or modified cholesterol. As we’ll explain, this is something that the body really doesn’t do on its own, and when you provide this capacity, we can do interesting things.
We have two lead candidates that we primarily focus on: we work on AAV delivery and also build cells that can be delivered as a cell therapy that are equipped with CDP. We also do some work on lipid nanoparticle delivery of mRNA, which is quite fashionable these days and has utility in some situations.
Our most interesting results to date: We have managed to produce a near holding of atherosclerotic plaque lipids in a mouse model of atherosclerosis with a single treatment of CDP. In the case of non-alcoholic steatohepatitis, NASH, a sizeable problem that’s somewhat outside the remit of aging, but very clearly related to cholesterol. In NASH prevention models, we’ve shown quite dramatic reductions in in pathological measures as well as an improvement in glucose metabolism or reduced insulin resistance, which is hard to do; nobody’s really done very well on that front with regard to NASH.
As I said, primary atherosclerosis, this is the problem that kills a lot of people worldwide. Atherosclerosis, in a nutshell, is a problem of macrophage dysfunction, really. Macrophages are the immune cells that are supposed to stop this problem from happening, and they do when you’re young.
They do it very well; nobody who’s young has these horrible fatty plaques building up in their arteries and killing them. That’s because your macrophage cells are doing a good job at catching all of this cholesterol that ends up in your artery walls and throwing it back into the bloodstream. When you get older, you have increased oxidative stress, and the oxidization of lipids really works a number on your macrophages; they’re not equipped to handle it at all.
You get increased dysfunction, inflammation, and failure to remove these lipids, and, in fact, eventually the macrophages start dying and make the plaques ever bigger as you go along. Eventually, your blood vessels rupture or become blocked, and you die. It’s very straightforward, very mechanical, and very fatal.
The degree to which it is fatal is the degree to which you have plaque. If you have too much of this stuff, your mortality is huge. You can see in the bottom right there, that’s a big difference. That really reflects the vulnerability of your blood vessels to pressure-induced rupture or blockage and immediate horrible consequences thereafter.
Unfortunately, most of the present approaches, in fact, nearly all of the available present approaches do very badly when it comes to reversing this determinant of death. You can slow it down; you can’t really reverse it. The current approaches, I’m sure you’re all familiar with statins.
Many of you will know about the the next generation of technologies such as PCSK9 inhibitors, which are far more capable than statins of lowering blood cholesterol. All of these approaches really target the amount of cholesterol in your bloodstream, and by reducing cholesterol overall, you also reduce oxidized cholesterol, give your macrophages a little more breathing room, and thereby you get this mortality reduction, but that’s all you get.
You don’t get a reduction, you don’t get a reversal of plaque, and that’s a big problem for many of these people whose diseases identify way too late when they’re in a very serious state. They can’t get back from that state, and as the prices on the right here show, there is a tremendous appetite for doing better. Nobody knows how well the AMGPTL3 inhibitors are going to do, but everybody wants them to be better.
Therefore, here we stand with a half-a-million a year price tag for genetic forms of accelerated atherosclerosis. We have to do better than this; we think we can do better than this. If you wanted to do a taxonomy of ways to address atherosclerosis, if we cut out some of the very minor things that are happening on the edge of the community, for the sake of simplicity, there’s only really two ways to go.
You either go to the liver, where most of the cholesterol outside the central nervous system is manufactured, and then it’s delivered to the rest of the body via the bloodstream, and you try to intervene in the liver. This is a really convenient location, because if you take a drug, most of it ends up in your liver, which is why liver diseases are such a popular area of development, it makes delivery very easy.
The other place to to intervene is in the macrophages themselves. As I said, this is a condition of macrophage dysfunction. It’s not really a condition of excess cholesterol; it’s the excess cholesterol causes macrophages to become dysfunctional.
Nobody does this other than us, to the best of our knowledge. There’s certainly rumblings in the research community and some interesting programs that are very early stage, but we think that that’s a good way to go. Which is not to say that you can’t make some improvements by going and tackling the liver itself by either making it make less cholesterol or take up more cholesterol, whatever works to get less cholesterol in the bloodstream, and at that point, you’re going to get these 20% reductions in mortality.
What do we do? We make cells able to do this: in short, take cholesterol, and reduce it into a generally recognized as safe catabolite that gets kicked out of the cells and quickly removed from the bloodstream.
Cholesterol is like energy; the body doesn’t really create it or destroy it to a first approximation. It does shuttle it around a lot. That gives rise to these Rube Goldberg systems that are prone to failure in late life or if you have genetic disease and you end up with too much cholesterol somewhere and you get pathology as a result.
There’s actually a lot of conditions where you start to see, “Wait, this is a problem of too much cholesterol in this one place in the body, maybe we should do something about that.” You can’t by manipulating existing human biochemistry, because we don’t break down cholesterol, as cells are not equipped to do that. They’re equipped to to package it and throw it around and store it and get rid of it and pick it up but not change it into something else.
We have two therapeutic modalities, as I mentioned earlier. When we’re targeting the liver, which we do, we’re using something along the lines of an AAV-based gene therapy, where we deliver this to the liver and that causes salutary effects.
Alternatively, we are making our own macrophages. We don’t want to edit macrophages in the body because editing macrophages makes them angry. It’s, in fact, very hard to manipulate macrophages safely without turning them into M1 phenotype macrophages that just want to rampage around and secrete inflammatory cytokines, which is sort of a challenge.
It’s good for cancer if you do that, but you’re not going to see many macrophage therapies outside that that don’t involve making induced pluripotent stem cells. This picture here is actually a bunch of our CDP-expressing pluripotent stem cells on the verge of being differentiated into CDP-expressing macrophages. We have a whole bunch of these stacking up in our incubators right now.
In the context of atherosclerosis, when I say atherosclerosis, I really mean three separate conditions. There’s the wild-type atherosclerosis that everybody has: item A here. Then there’s also the hypercholesterolemias, and the hypercholesterolemias are genetic conditions, where you either have one copy or two copies of the relevant gene mutated. In this case, it’s the LDL-R gene, which helps the liver take up cholesterol. If the liver can’t take up cholesterol, then, well, you don’t have an enormous amount of cholesterol in your bloodstream, and you’re going to get atherosclerosis very early; these people are discovered late, they die young, and there’s very little that can be done for them at this present time.
There’s a tremendous amount of interest in developing ways to help these people. Fortunately, if we can help them, we can also treat atherosclerosis itself, and by the alchemy of the way in which modern development works in the regulated environment, we are heavily incentivized to go after these orphan conditions first and then adapt our package to atherosclerosis. We believe that the AAV approach, which is enormously expensive, by the way, in terms of manufacture, is best suited to an orphan condition like HoFH.
If we get the macrophages working, when we get the macrophages working, we can use that for anything, it doesn’t matter to us how your plaques came about, we’re sending in the macrophages and they will dismantle it, which puts us in a very strong position, I think, in terms of the development of the company. If you can take your treatment straight from a an orphan condition to a very widespread condition without any really further development, that’s a good place to be. It gives you the best of both worlds.
I will just talk about the the liver side of things. First of all, I’ve really shown this before, this next one is a slightly more detailed version of what we’ve set aside to tell people we’ve achieved. We take mice, a mouse model of atherosclerosis, which have the APOE gene knocked out, it makes it difficult for them to correctly maintain their arteries, and they get atherosclerosis as a result, when they’re fed a high-fat diet.
We put them on the high fat diet for long enough to develop atherosclerosis. We give them a high-dose AAV carrying CDP and wait a month. The result here is, what you see is, something like a halving of plaque lipids, which you can actually see in the cross sections of aortic root on the left there.
The fiddly little bits in the middle of those pictures, those are valves, and the red is lipids. Way less lipids in the treated mice, and this is a really impressive result. It’s very fast. Statins can’t really do this to a first approximation, and if they did, it would take a year. It’s a really good demonstration that we’re on to something that can have a very large effect when we translate it into humans.
Now on the macrophage side of the house, we are presently stacked full in our incubators of induced pluripotent stem cells taken from mice and humans. We are converting them into these macrophages step by step. We’ve done this for many cells; we put CDP into many cell types.
The beauty of this is because it’s a de novo pathway, it’s an entirely new thing that you put into cells; you’re not really dependent on what type of cell it is or where it comes from. So 293Ts here are a workhorse cell, a human cell type that everybody uses to test things out, because they’re kind of good for that. U937s on the right are our type of monocyte line; monocytes are the precursor to macrophages. They change, they sit in the bloodstream, come from the spleen, they become macrophages when they enter tissue.
As you can see, the result is exactly the same. It goes there and it turns cholesterol into the satellite. We’ve many other examples of cell types where you get exactly the same, but that would make a very boring diagram here.
CDP expression in cells is non-toxic unless you’re a cancer cell, in which case, it makes it less happy. In normal cells, you’ll see that the cells don’t really have any effect in terms of cell death under exposure to cholesterol or just normally. This is great; it’s a very safe approach to modifying cells to make them achieve the result you want to achieve.
Importantly, one of the results we want to achieve is to remove foam cells from the picture. Now, a foam cell is a macrophage that has become dysfunctional in the context of an atherosclerotic plaque and is full of cholesterol and lipids. It’s called a foam cell because it deposits the lipids into bubbles inside it, and you get the foamy appearance.
On the left, you see a bunch of RAW264 Mouse macrophages that are not doing so well; they’ve ingested a bunch of cholesterol, and they can’t deal with it. The cholesterol is fluorescent in this case. It’s very easy to see that these are unhappy macrophages. They’re pathological; they will die soon.
If this were a plaque, they’d be expanding the plaque by adding their mass to the plaque itself when they die and also secreting inflammatory signals that attract more macrophages to suffer the same fate. In principle, if you do what we do on the right here and give these macrophages CDP, they no longer become foam cells because they can break down the cholesterol. In theory, they just keep going and keep doing their work and keep on maintaining the plaque. We’re maintaining the blood vessel and removing the plaque bit by bit.
Our end goal is to get these macrophages into people one way or another and leave them there for long enough that atherosclerosis reverses itself completely. This is, in principle, a very feasible goal. We hope to have some great data on this from animal studies later in the year. We’ve already injected suitably manufactured CDP-expressing macrophages into mice; first results soon.
When we do take this to the clinic, we are looking at universal cell lines. With macrophages, unlike T cells, or other immune therapies where you can take a patient cell and manipulate them and put them back, you can’t do that with macrophages. Macrophages do not want to be manipulated; they get very, very upset. They turn inflammatory; they will do things you don’t want to do.
What you have to do is make a universal cell line, you have to make a line of macrophages from iPSCs that are in some way modified to be invisible to the immune system such that you can put macrophages from a line derived from person A into persons B through Z. There’s a number of companies doing this, and we’re in collaboration with some of them and we’ve talked to most of them, so I don’t have to mention names; you guys who know know who these guys are. The attractive part of this, the many attractive parts of this, one, monocytes and macrophages automatically home in to plaque; you can inject them anywhere, and they will go to where they’re needed.
They last for months, and once you’re at a point where you’re generating cells from a line, you’re looking at a cost that’s very similar to present-day stem cell therapies, you could get this down to five figures or maybe even four figures, once you get into the realm of economics of scale. It’s a very attractive mode of therapy.
We have a proprietary method of creating macrophages from iPSCs. I would venture to say it’s not hard but also very hard. Everything to do with cells is really obnoxious to work with. Don’t work with cells, children, dogs, you’ll have a hard time of it, but we produce these things reliably and robustly and they’re looking pretty good.
Who we are? You guys know me. I’ve been around the field for a while, I write Fight Aging, I’ve invested, I’ve helped raise money for various nonprofits like the SENS Research Foundation.
Bill Cherman, also an investor with a finance background, is my co-founder. Mourad Topors is a friend of the inventor of CDP and a very skilled and experienced PI with Pfizer and Harvard in the cardiometabolic space.
Bobby Khan is a as a physician and specialist in atherosclerosis who has put drugs through the FDA already and keeps us on the straight and narrow on that front. Our advisors include Richard Honkanen, who invented this technology, Graham, who many of you know from the conference circuit, keeps us advised on the matter of how you make macrophages happy or unhappy. Andrew and Babak are specialists well-known in the field of liver pathology and cardiovascular disease, respectively.
Now, I did say that I was going to say something about NASH and left it for last. NASH is very prevalent for a condition that is really a consequence of obesity for nearly everybody who suffers it. We live in an age of obesity and, as a result, there is a very large market waiting for whoever can produce a way to really help with NASH. One of the reasons that this is such an interesting area, it’s completely unrelated to aging really, but one of the reasons this is a very interesting area for pharma is that there isn’t really a good way to deal with it right now.
NASH includes a whole range of unpleasant things, some of them are related to aging that we don’t have a good handle on, which is chronic inflammation, fibrosis, insulin resistance, things that are currently challenging to deal with. While NASH would be an incredibly minor problem if everybody would just eat less, it’s currently a major problem because there doesn’t seem to be any likelihood of people eating less in the near future.
What can we do? We’ve run a couple of models over the past six months. One delivering AAV CDP, and one an experiment with lipid nanoparticle delivery of mRNA to try to get to the liver, and we see that we can reduce quite reliably, and by a sizable amount, some of the issues associated with NASH.
In NASH, for example, stellate cells in the liver are very active, and this is associated with fibrosis; we’ve reduced that quite comprehensively with a single treatment with AAV. Macrosteatosis is the formation of droplets of lipids in the liver, which is, of course, not a good thing and not what you want at all. A very pathological liver is just a lump of fat, it’s really not good. Getting rid of that problem is something that’s also a challenge in the present medical environment.
Most interestingly, however, we can reduce insulin resistance; this is a high-level property of the liver and the system as a whole. We can address this robustly and significantly in a NASH model. The widely accepted NASH model is very interesting and has interesting implications for the state of science on NASH and liver pathology as to the degree to which cholesterol accumulation in hepatocytes is a significant source of pathology in this disease, which has been a point you could argue either way in the past.
One of the things I repeatedly say to people is that it is very hard to understand in aging, or indeed any other condition, which of the items, which of the mechanisms you can identify are actually the most important; the only way to really do it is to go get rid of one of those mechanisms in isolation and see what happens.
That is what we’re doing here. We have a way to, in isolation, get rid of excess cholesterol. We are seeing in these studies, and in this one and in our results in an atherosclerosis model, we see just how important that is to pathology. With that, I will say thank you.