The Repair Biotechnologies View of Cholesterol Pathology at the 2023 Foresight Longevity Workshop

I attended the Foresight Institute's 2023 Longevity Frontiers Workshop earlier in the year. This event series provides a chance to make connections with some of the longevity industry figures and academic researchers in the field of aging that are associated with the Bay Area venture and futurist communities. The format this year was rapid-fire seven minute presentations and longer discussions; the presentations are shared online. I presented an informal, abbreviated version of the Repair Biotechnologies viewpoint on the role of cholesterol in aging and disease, trying to cover at least the important points in the time allotted. This viewpoint is informed by our evidence for reversal of atherosclerosis and NASH in animal models following application of a gene therapy to selectively clear only pathological, excess, toxic cholesterol in tissues, which we view as a demonstration of the importance of localized excesses of cholesterol to these conditions.

Reason | Repair Biotechnologies @ Longevity Frontiers Workshop 2023

What are we going to do today? We're going to think differently for seven minutes about cholesterol and aging. I'm not going to mention LDL once. So! What goes wrong in this whole process?

Problem one: this is a problem of cholesterol transport. Localized excesses of cholesterol form when cholesterol transport is disrupted. If you are obese, you are disrupting everything everywhere, your body has nowhere left to put cholesterol, the situation promptly goes south. Otherwise, more subtle effects of aging operate on the cells that are needed to sustain cholesterol transport, leading to less pervasive but locally similar issues.

Problem two: oxidative stress that occurs with aging causes the creation of forms of toxic cholesterol. These are outright disruptive to tissue function, and are a problem that should be gotten rid of.

In both cases this is not really the present dogma in terms of how treatment is targeted or works for conditions related to cholesterol, which is why I'm suggesting that we need to think differently about this. Just focusing for a moment on problem one, the broken cholesterol transport system: as you may or may not know, cholesterol manufacture is expensive, energetically expensive, therefore we evolved not to do it in situ, where the cholesterol is needed. It is manufactured in the liver, largely, with a fifth of it coming from the diet, and then you have a Rube Goldberg system that transports this cholesterol everywhere it needs to be. It is needed everywhere! Every single cell in your body needs cholesterol.

When it works, great! But we can say that about everything in the young body. Aging degrades this system, and particularly the macrophages that are responsible for taking this cholesterol and removing it from where it gets stuck in your blood vessel walls. That is the real problem here, though certainly others exist due to the ability of aging to mess up everything that looks like a complex system.

A localized excess of cholesterol, however it comes about, is toxic. Cells have a limited ability to stash this excess as esterified cholesterol, or refuse to take it up. That capacity can be very easily overwhelmed by physiologically achievable levels of cholesterol - get a little bit fat, and you are causing toxic harm to yourself. Get old, and there is toxic harm taking place due to problems, such as macrophage dysfunction, that reach a tipping point and lead to accumulations of cholesterol in your blood vessel walls.

Excess intracellular cholesterol disrupts cell function and kills cells. Once the excess overwhelms the ability of the cell to esterify it, it becomes free cholesterol, and free cholesterol is explicitly toxic to cell function. This is what happens in the old body, and this is what happens in the obese body. In obesity, you get the very prevalent non-alcoholic steatohepatitis, NASH, which is a silent disease, and very problematic because it is irreversible at present. In the case of your dysfunctional macrophages in your blood vessel walls, you get atherosclerosis, which, coincidentally, is also largely irreversible at the moment. One you have developed a atherosclerotic lesion, that lesion isn't going away, and there is nothing you can do about it using the present standard of care.

These are both very large potential markets, if you can find a way to deal with this problem. But let us look at the other issue for a little bit, our problem two. The other issue is that inflammation and oxidative stress, which go hand in hand in aging, largely due to mitochondrial issues, produce altered, toxic forms of cholesterol. The more oxidative stress you have, when your dysfunctional mitochondrial produce more oxidative molecules than the body can handle, the more that those oxidative molecules are going to oxidize lipids.

That causes problems in many ways, and one of the problems that you are probably all familiar with, because of the work of Cyclarity, is the growing presence of 7-ketocholesterol. This is one of the worst of these oxidized lipids. It is implicated in a whole range of conditions in aging. One of those conditions in atherosclerosis, because 7-ketocholesterol punches above its weight, there are only small amounts of it relative to normal cholesterol, when it comes to the ability to disrupt macrophage function in arterial walls. But again, remember that an excess of normal cholesterol will achieve the same outcome without adding 7-ketocholesterol. 7-ketcholesterol is adding insult to injury on top of that.

How do we address both of these two problems? Cyclarity is addressing the second problem, and hopefully their approach produces a large effect size, something that you can add on top of statins. The way that you address both problems is by selectively clearing cholesterol. But! You can't just go into the body and clear cholesterol. It is in cell membranes. If you put enough cyclodextrins into the body for the small molecules to grab all of the cholesterol out of lesions in the blood vessel walls, the you probably also just turned that patient's blood to mush and killed them along the way, as the treatment will also grab cholesterol from cell membranes.

Thus we need something smarter, and that is what we do at Repair Biotechnologies. We have something smarter, a combination of human enzymes that act to safely break down only the excess free cholesterol inside cells - the non-esterified toxic cholesterol. It also happens to work on modified cholesterols, such as 7-ketocholesterol, when they get taken up into cells. Those molecules are also broken down. We have demonstrated that this produces very profound reversal of both NASH and atherosclerosis in animal models. Localized excess of cholesterol is the major mechanism by which these diseases operate. You have this local excess of cholesterol that produces toxic free cholesterol inside cells.

In the case of macrophages it disrupts their function, makes them foam cells, stops them doing their job, advances the tipping point to enable the growth of atherosclerotic lesions that will kill you. In the case of NASH, there is so much cholesterol in a NASH patient that it is just messing everything up: the whole liver is a toxic mess. But specifically, it is a toxic mess because of excess intracellular free cholesterol. If you can get rid of that, then everything else becomes much less of a problem.

That is this short topic in a less-than-seven-minute nutshell, Repair Biotechnologies and why you should think differently about cholesterol and aging. Why you should think differently is because if you clear free cholesterol, you observe profound reversal of conditions that cannot presently be reversed. Anyone who is interested - you know where to find us!

We have made considerable progress since presenting at Foresight last year. We work with lipid nanoparticle (LNP) / mRNA delivery systems at the moment, and we have used them to produce quite extensive reversal of NASH in animal models of the condition. On the strength of this work, we submitted an INTERACT meeting request to the FDA earlier this year, and were told to go straight to a pre-IND meeting. We plan to submit the pre-IND meeting package in, say, Q4 this year.