344 oki oconnorr
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Kevin Folta: [00:00:00] Hi everybody. And welcome to this week's podcast today. We're going to talk about some of the issues around. Long-term human disease and some new solutions to increase longevity. And we can really start about how do, how do modern companies design new molecules to defeat some of the problems that plague us as we grow older?

One good example is cardiovascular disease that around the world is a leading cause of death. And whether you're talking about, you know, the heart or maybe an aorta or something, Even stroke is based on a vascular event. So the health of the circulatory system is a really critical part to solving these problems.

That's just one example, and we've always relied on drugs, upfront things to control blood pressure, maybe statins to control the contributing factors. To say cardiovascular disease. So today we're going to talk about a company that is working with [00:01:00] small molecule design, with the idea of targeting some of the molecules that, that accumulate as we age that are contributing to different issues like cardiovascular disease or Alzheimer's or other afflictions that appear to be that seemed to come on with a.

So today I'm speaking with Matthew O'Connor, who goes by oaky. So Matthew oaky O'Connor, he's the co CEO and co-founder of underdog pharmaceuticals out in California. So welcome to the podcast. Dr. O'Connor. 

Oki O'Connor: Thank you very much, professor. It's a, it's a pleasure to be, 

Kevin Folta: and I was really nice to talk to you.

I'm excited because this is a little bit off our beaten path and kind of the direction I'd like to go with the podcast as we go into our eighth year now is not just talking about these big breakers and biotechnology. But some of the interesting extensions around new drugs and new ideas and new approaches to solving important problems.

And so when your big interest seems to be around this idea [00:02:00] of how do we live longer and more healthier, and until COVID life expectancy was consistently rising, we at least in the industrialized world. So why do we want to extend that? And what are your big interests in the area of London? 

Oki O'Connor: Right. And in fact, including with COVID the biggest risk factor for dying from COVID is, is age.

So aging is is, is killing everyone today, which hasn't always been the, in the case in the, in the distant past. But for the last hundred years that is increasingly been the case. So all the major killers today including COVID, including. Cardiovascular disease and even respiratory disease and cancer diabetes dementia Alzheimer's disease.

Parkinson's these are all diseases of aging, the biggest risk factor for all of those diseases and many more is aging itself. So for the next frontier of medicine, I [00:03:00] believe that. We have to look at the root causes of aging and how do they cause the diseases and disabilities of aging. If we want to keep making the kind of great progress that we've been making over the last hundred years in improving human health and lifespan, which has, as you just said, increased tremendously over the next hundred years, but we have to tackle aging itself.

If we want to keep that positive. Yeah. So there's a couple 

Kevin Folta: of thoughts here because aging is, you know, as sort, as calendar pages come off, there are likely changes that are happening at say, even the level of DNA, epigenetic changes, things that are happening with modifications of DNA or different genes are turned on and off in ways that are a natural part of human senescence.

And it seems like your company has been targeting a lot of the intermediary molecules, which are. Maybe a result of those processes, or maybe come on as part of this senescence process, which is, which is a natural part of animal development. I mean, we see it [00:04:00] everywhere from mice to dogs, to humans just on different timescales.

So what is the benefit of targeting these kinds of intermediate molecules that seem to usher in, or at least be associated with the aging? 

Oki O'Connor: Right. And they're only, I don't want to try to claim that that, that the, the niche that we're targeting is the, be all end, all of the aging process. It's only part of it.

And as you pointed out, there's many other kinds of damage that accumulates with a. And the accumulation of toxic biomolecules with age in various cells and tissues is, is one part of the puzzle that we're going after. And we decided to, to, to start here. Because it it, it's a it's a bit of a low-hanging fruit that we felt like we could target, but it's also something that has been ignored.

Mostly in, in medicine. There's not a lot of drugs targeting. Targets like the kinds of like the main target that we're going [00:05:00] after, or some of the other targets that we're thinking about going after later. And and then also with the class of drug that we're developing it's a, it's kind of a new approach to going after this, this sort of class of targets.

So and also we felt like it If you go after something that's just bad as opposed to say something that's both good and bad sake, like cholesterol you know, it can be too high, but it can also be too low. Right? You need some of it to survive, but if you have a toxic biomolecule that accumulates with age that is, is only giving detrimental effects, then in theory, if you have a perfect drug that has a, that that's on target.

You you'll never be able to overdose on it. You'll only be able to, you only reduce the, the bad stuff that you're targeting. So that was kind of our idea and philosophy in, in going after this, the way that we are. 

Kevin Folta: Yeah. See, this is a pretty intriguing concept to me that toxic bio-molecules it would seem like these things wouldn't be.[00:06:00] 

Part of our physiology because biology would select against them. Right? The things that survived would be the things that didn't accumulate these molecules and that eventually they'd be just part of evolution would go away. And I'd never really heard much about this. So what are some examples of toxic bio-molecules and can you give me maybe a really good disease where you can have a strong association specifically with a certain class of toxic biomed?

Oki O'Connor: Okay, well obviously the easiest place for me to start is where we are focused now, which is on oxidized cholesterol. And there there's one species of oxidized cholesterol that we spend most of our time on, because if you react cholesterol with a oxygen free, radical, then more often than not, you get the same.

Molecular species over and over again. You get seven Quito cholesterol, which has a single extra oxygen [00:07:00] atom on it in that seven position around the ring structure of the cholesterol molecule. And that molecule is not. Other derivatives of cholesterol that are signaling molecules in your metabolism, in your biochemistry that one is not coded for in your, in your DNA or in your in your metabolism.

It's not created intentionally like a steroid hormone or some of the signaling Oxy stairwells. It happens accidentally when you have free radical damage of cholesterol. And so. That, that will happen all the time. If you have oxygen around cholesterol is just going to happen to a certain percentage of the cholesterol that's there.

So it has no useful purpose, so we should just get rid of it. It's very toxic. It's very, atherogenic. We actually wrote a, a whole review article about it and published in 2020 that people can go look up called [00:08:00] Seven Quito cholesterol in disease and aging published in a free radical biology and medicine.

And we go over all the different diseases that this particular toxic molecule is implicated in, which happens to be a lot of the diseases of aging that that it's accumulated in. Is it the single cause for all of those diseases? No. But it is, it is a, it is a factor in them. So why hasn't.

Evolution selected against it. That was another part of your question. And part of that is about the evolution of aging itself. It, the, the, the idea is that most of the pressure in evolution comes from. Reproduction. So you have to survive to reproductive age and you have to you know, fertilize or, or produce offspring.

And then you in, in many species especially in ours, you need to survive long enough so that your offspring can survive. And then you are evolutionarily successful. But other than that evolution [00:09:00] doesn't really care about you. And so if it doesn't kill you before. You've given your, your offspring enough chance to survive and reproduce themselves.

Then there's not a lot of selective pressure to, to solve a problem. And so if you have something like oxidized cholesterol that accumulates slowly over decades, then there's there's little or no selective pressure against it. And so in the human body there is some capacity to deal with oxidized cholesterol and the liver.

The hepatocytes can to, to an extent metabolize oxidized cholesterol, but most of the cells and tissues in your body just haven't bothered to presumably because that would be energetically expensive. And it doesn't need to worry about that until you're in your fifties, sixties. Okay. So this 

Kevin Folta: idea of oxidized cholesterol, you say it comes from this idea of free, radical attack on cholesterol and cholesterol.

So where [00:10:00] does, where do the free radicals come from and do we accumulate more free radicals or have less ability to scavenge free radicals as we. 

Oki O'Connor: So it's actually a difficult question. Most I in my previous life, I spent a lot of time doing mitochondria research and and so most people think that most free radicals come from your mitochondria which I think.

By and large is true. But the question of whether oxidized cholesterol comes from the mitochondria or whether free radicals that cause oxidize cholesterol that the the oxidants come from the mitochondria is actually a surprisingly controversial. And part of the reason for that is that there's relatively little cholesterol in the mitochondria.

So exactly. Th that, that sequence of events is still a little bit of a mystery but it's likely that the there's free radicals reactive oxygen species leaking out of dysfunctional or damaged [00:11:00] mitochondria with age that are reacting with cholesterol and. In the cytoplasm, in the plasma membrane and that and that that's the, the original source.

But you know, you can get free radicals from from other sources as well. Leaky plasma membranes can also be a cause of free radical production. And so how 

Kevin Folta: does this seven keto cholesterol relate specifically to some sort of pathology? 

Oki O'Connor: Well seven Quito, cholesterol, or seven Casey or oxidized cholesterol, her ox call It it's involved in many diseases in many tissues.

It it accumulates, especially in atherosclerotic plaques where it's thought to be highly atherogenic. And if you find large quantities of it accumulating in the necrotic core of the plaque and in foam cells, foam cells are macrophages that get recruited. [00:12:00] To to plaques that are supposed to go and clean up the, the lesion, but they end up when they go and they try to eat all of the lipids and some of the debris that they find at the plaque and they accumulate too much oxidized cholesterol.

That gets into their license zones, shuts down their ability to metabolize lipids, and they keep eating though. And they balloon up into the cells that look like little pieces of styrofoam as where they got their name foam cells. And they end up contributing to the plaque rather than rather than resolving it.

So. That's the most glaring example of a disease that seven KC or oxidized cholesterol is involved in. It's also involved in Alzheimer's disease by similar mechanisms likely is also involved in macular degeneration and fatty liver. Okay. 

Kevin Folta: So this is a type of cellular event that's happening. It's based on this oxidized form of [00:13:00] cholesterol, leading to other types of cellular events that lead to these.

What seemed to me to be kind of a constellation of long-term maladies that all kind of have the same at least commonality of this oxidized cholesterol. So what is the solution that you've proposed anyway, to be able to deal with this particular. 

Oki O'Connor: Right. So I've actually been thinking about this problem a little bit for about 20 years.

I saw a wonderful talk on oxidized cholesterol in in in atherosclerosis and how it causes foam cells about 20 years ago when I was in graduate school. So I've been thinking about it since then, but I . My previous foundation, the sens research foundation, where I was vice-president of of research until I left to found underdog we were trying to find solutions to this problem of oxidized cholesterol in aging and and in [00:14:00] cardiovascular disease.

And I started looking into the, the literature from. For sort of cheap and easy hacks, if you will, to go after this and found work in the eighties and nineties of these molecules called cyclodextrins that are these really interesting cyclic carbohydrates that. Certain kinds of them are the right size and shaped to bind a sterile in molecule.

And so there were in vitro experiments in the eighties and nineties looking at different kinds of cyclodextrins and their, their properties and their ability to interact with with cholesterol and. Cholesterol like molecules and that's what started to lead me towards thinking about what kinds of cyclodextrins could do this, which led to doing experiments on that in the lab and finding out which ones that were already available out of the dozens [00:15:00] of existing commercial available cyclodextrins could bind oxidized cholesterol.

Specifically and with high affinity. And from that, we could learn how to build a better cyclodextrin that could bind our target with much higher affinity and specificity than any of the sort of cheap generic ones that are available in the chemical. 

Kevin Folta: Yeah, so, and that's really where the magic happens.

And so we'll pick up with that. On the other side of the break, we're speaking with Oakey O'Connor, he's the co CEO and co-founder of underdog pharmaceuticals, and we'll figure out the relationship with underdog and exactly what that means to a, this is the talking biotech podcast by Culebra. And we'll be back in just.

And now we're back on collaborative talking biotech podcast. And we're speaking with Dr. Okie O'Connor he's the CEO or co CEO and co-founder of underdog. Pharmaceuticals is my [00:16:00] favorite cartoon is a kid. So w w why underdog 

Oki O'Connor: pharmaceuticals? Right. So the the history behind the name is that my co-founder Mike and I were sitting around trying to think of a good name for, for this company and one we're both dog lovers.

And, but too, since our approach is looking at an underlying cause of disease the under dog underlying causes of disease is part of the inspiration and third that since we're taking a bit of an unusual approach, since we're trying to. Bring a different approach to, to pharmaceutical development from, from taking this kind of angle that makes us underdogs or at least it it did when we were first getting started.

And so we, we felt like we were the underdogs going into this and that we had something to prove. So that's where the name came from. 

Kevin Folta: It's [00:17:00] good because you know, most, most companies are trying to think of something. You know, something that has an edge of a sciency sounding thing and, you know, and usually a lot of X's and Y's, and so, you know, underdog sounded interesting.

And especially if you package your product, if you do have a therapeutic you know, orally administered pill or something to put it in a little ring, like they had on the underdog, That's probably why that was, it's probably why that was discontinued because it take the pills and all of a sudden you get, but feel better.

It's kind of the opposite idea, that opposite messaging of Popeye that you know, to kids. But anyway, I'll just so we were talking before about this idea of these cyclodextrins and cyclodextrins being these cyclical, carbohydrates that bind to. Cholesterol or they bind, they, so generically, they bind to all cholesterol or just the oxidize.

Oki O'Connor: Well, it depends on the cyclodextrin. So there there's a bunch of different varieties and flavors. There's, there's three different basic cyclodextrins alpha beta and [00:18:00] gamma. And those are just three different sizes. So the, the medium size ones are the beta cyclodextrins and those are the. Size and shape to fit a cholesterol or a cholesterol molecule inside of them.

And so there's a bunch of varieties of beta cyclodextrins that bind cholesterol or different cholesterol, derivatives, or cholesterol like molecules with, with different affinities or specificities. So that's where we started and started iterating. 

Kevin Folta: Okay. So, so, but w where did they come from?

I mean, are these things that we encounter naturally in food or anything like that? 

Oki O'Connor: They they're they're made by some microbials naturally. So the, the core molecules of the alpha beta and gamma forms are made enzymatically. So they, they get mass produced by enzymes that were derived from microbials that that, [00:19:00] that originally invented the molecules evolutionary.

But after that after you have one of those three, then you can synthetically modify them to have different properties such as greater solubility that can confer. That comes in for a safety. So if you take unmodified, beta cyclodextrin and injected intravenously, it'll be very toxic because it's hydrophobic and it will aggregate and and cause damage to your kids.

But then if you modify it in certain ways to, to make it a more soluble, then all of a sudden it can be one of the least toxic molecules in the world. And and there's certain cyclodextrins like hydroxy propyl, beta cyclodextrin. That is one of the most common. Excipients for delivering drugs in medicine today.

And it's it's extraordinarily [00:20:00] safe up to grams per kilogram of body weight injected other uses for cyclodextrins there's industrial uses for cyclodextrins. They're they some cyclodextrins are approved for use as, as fiber supplements. So you can eat the. You don't absorb them. If you eat them you, you pass them or right through your system.

And they, they don't they don't really interact meaningfully with your, with your metabolism. So they, they kept some really interesting properties. They can be engineered in all kinds of different ways. You can build super materials and matrices with people have made self-healing gels with them.

They've made super hot. Paints somebody in Japan built an entire car made out of only cyclodextrins. So they're extremely versatile and and engineerable molecules, and they already have a safety profile that the regulators can, can understand and get behind. That's it, those are all the factors that made them attractive to me as a, as drug development [00:21:00] platform, how are they 

Kevin Folta: engineered so that they can work specifically to do the work that you want them to do in mitigating the effects of oxidized club?

Oki O'Connor: Right. So the, the big breakthrough for us was wa was taking a beta cyclodextrin molecule and and figuring out the w when we were studying that the cyclodextrins in their ways to, to bind to our target oxidized cholesterol, we figured out that the most stable. Confirmation of of the cyclodextrin with the with the Oxy sterile was two cyclodextrin molecules encapsulating together around one.

Oxidized cholesterol molecule and in a certain confirmation in a, in a head-to-head confirmation so that they were, they [00:22:00] were wrapping around the the, the steroids in a, in a, in a very specific way. So we asked ourselves what happens if we, if we force. That interaction by joining two cyclodextrin molecules together in that head-to-head confirmation that they're naturally binding to the Oxy sterile with w what if we joined those together in a dimer, but leave it with the flexibility so that it could still wrap around the the target.

And so we made a prototype and. And, and and mixed them together and found in our, in our first in vitro assets that we, we increased the activity of our cyclodextrin molecule by several not just several fold, but several orders of magnitude. So that's when we knew that we were onto something and we started iterating from there on how we joined the molecule together and what kinds of derivatives we put on the [00:23:00] outside of the cyclodextrin molecule itself to give it the exact rights Shay.

That it's it sort of grabs onto the target oxidized cholesterol specifically, and leaves alone, other related molecules that that you wouldn't want to get rid of. 

Kevin Folta: Yeah. See, that's the that's what was my next question is the specificity because cholesterol and other sterols are so critical to the manufacturer of hormones and other things, is it really.

Somehow in silico modeling process that allows you to predict specific molecular interaction with the oxidized cholesterol versus other states. 

Oki O'Connor: Yes. We took a, that kind of iterative approach between in silico modeling of cyclodextrins and bench chemistry and rational drug design to do it.

So we started modeling the drug and th this was actually started [00:24:00] after we had this idea and we were sort of, you know, doing one at a time playing around at the, at the bench. I had this. Summer student Mia Anderson, who came to me in 2017 and she had this idea you know, Hey, I took a class in, in undergrad you know, modeling you know, receptor, ligand interactions, you know, psychometrics.

Kind of look like receptors and R are the, you know, the oxidized cholesterol route looking at as kind of a login. So maybe I could hack one of these systems for for binding cyclodextrins and said, what do you need? She said, I need a hundred dollars for a software license. I said, go ahead. And by the end of the summer we had a whole new approach for.

For, for looking at this and and that eventually led to the, the, part of the inspiration for this for this dimerization idea that we had and helped us iteratively build some of these molecules. And so then we started making prototypes, testing them in some very simple in vitro binding.

[00:25:00] Assay's going back to the, in silico modeling seeing if we could tweak the the molecules a little bit more you know, synthesizing some are testing them at the, at the bench until we have. One that that was preferentially. We were selecting for something that could bind oxidized cholesterol, seven Quito cholesterol in particular and against dimers that would bind cholesterol, not to say that our drug doesn't mind cholesterol.

It just very preferentially binds seven Quito cholesterol. Yeah. 

Kevin Folta: Was it the best, a hundred bucks? 

Oki O'Connor: By far, I can't think of anything else that that I've ever spent money on that's that, that has yielded a, has as much value as that. Yeah. These 

Kevin Folta: days that'll get you a tank of gas in a mountain. Do you know?

And that's. That's a, that's pretty amazing. So the, I guess the next big question and thinking about this is if you're able to sequester this oxidized form of cholesterol, which is the one that leads to the pathologies, isn't able to actually [00:26:00] reverse the effects of things like atherosclerosis or there, you know, if you say it plays roles in Alzheimer's, things like that, does it reverse it or is it just help limit the accumulation on the.

Oki O'Connor: The idea is that it will reverse it. So what we've been able to show in cell culture models was first could oxides cholesterol is, is very toxic to cells. Any cell type that you incubate with with oxidized cholesterol is at a fairly low dose of of seven cases. We'll we'll kill pretty much any cell type that, that you can culture in a dish.

And so the first thing we tried was, well, if we, if we add in some seven KC and we add in our drug into the, you know, into the cell culture media, that the liquid. Broth that that the cells grow in a 10, we prevent their death. And the answer was quite dramatically. Yes. At at, at pretty low concentrations of [00:27:00] our drug.

We could prevent their death now. You might say, well, okay, you select. That's sort of a tautology because you, you created the drug to bind the target and then you put them in together. So it just, it just, you know, encapsulated the target and didn't let it get at the cells. Fair enough. But then what we did next was, was two really exciting things.

One is that we got some plaque tissue from. From humans who had atherosclerosis when they died. And we took that that, that plaque tissue fresh from a, from a cadaver and incubated it with our drug and measured the oxidized cholesterol inside of the. Before and after we incubated with our drug and we found that we could draw out in a dose dependent manner, huge percentages of the oxidized cholesterol in that plaque.

Not only that we could do it in an [00:28:00] incredibly short amount of time, which was a total shock. To me that we started out looking at hours and, you know, 24 hours and three hours and bizarrely, the 24 hours and the three hour curves were exactly the same. So. Then we did it for 15 minutes and that was exactly the same.

So the the system is coming to equilibrium extremely quickly. So it's, it's acting, it's doing what it needs to do and it's doing it really quickly. The next thing we did was we created foam cells in the, in the lab. So you take macrophages and you. You feed them some, some lipids. In our case, we do it in a way that we only need to feed them a little bit of oxidized cholesterol as opposed to a ton of Bach cholesterol like most people do.

You just need to give them a relatively small amount of oxidized cholesterol and. Turn into foam cells fairly quickly. So they balloon up. And what we did next is after that we they're, they're not [00:29:00] being fed the oxidized cholesterol anymore. That's sort of a permanent state. It's like senescence.

It's like cells. In essence, once you go foam, you don't turn back into a healthy living. Macrophage and what we've done and what we're still investigating the, the repercussions of this. And this is, this is all unpublished data. Now that I'm talking about W we were able to reverse the the fundamental aspect of phoniness is the is the lipid levels that that are in the cells that are these lipid droplets that accumulate inside of the macrophages.

We can make those go away after they've already appeared. So we're reversing the phone cell phenotype. So that's why we think we're going to be able to revert. Atherosclerosis and people who have art, who are having, which, which will be completely revolutionary if we accomplish it. That's a, that's never been done before.

Kevin Folta: Yeah. I guess maybe when, maybe I'm shooting a little bit far down the field with this next question, but [00:30:00] the relationship between atherosclerosis, lordosis and sudden cardiac death from cardiac myocardial infarction comes from plaque. And so is destabilizing a reversing, a plaques, structural integrity, maybe not such a great idea, or, you know, so am I barking up the wrong tree?

Oki O'Connor: No, that's actually a really good question. And you're, you're not the first scientist to ask in a question. And importantly the, the the regulators who protect the public safety are interested in, in that question. So. We, the there's already answers. We don't know that we would be causing a thrombotic event when when a plaque ruptures but we don't want to do that in any person ever.

So certainly we're going to tip toe into those waters and and only treat patients at first who have non-culprit plaques, which are, are. Plaques [00:31:00] that are not ready to rupture that that aren't in their latest stages that, that have a fibrous cap that are, that are ready to break off and and cause an ischemic event.

So w w we're going to err, on the side of of, of treating people who who, who don't have dangerous plaques at least at first that that we might rupture until we have an awful lot of evidence that we won't cause a rupture when we treat with our drug. 

Kevin Folta: Yeah. Maybe this is the pushback, you know, on the other end is why not just treat with things like statins to decrease cholesterol levels in the first place to decrease the amount of oxidized cholesterol.

Why isn't that approach or why is your approach better than what would be the more traditional 

Oki O'Connor: approach? Right. So that's the standard of care right now is that if, if you have. High cholesterol, high LDL cholesterol, especially and, or atherosclerosis that your arteries are starting to thick in.

You're going to be [00:32:00] prescribed statins or other cholesterol, lowering drugs, such as PCSK nine inhibitors. That's fine. But it doesn't. Reverse the disease. The disease is the lipids accumulating in the in the arteries and it is the plaque and the plaque is what reduces blood flow and what can break off and rupture as you pointed out before and caused the heart attack or the stroke.

So the stat, the, the, the, the cholesterol lowering drugs, such as the Staton. It cannot reverse that plaque. Once you have that plaque, if it's, you know, state J or state agency, it is what it is. You might be able to slow down or maybe in some cases that there was some claims that that, that if you can get LDL to, you know, really, really, really low levels that in, in some people that you might [00:33:00] stop the.

The the the growth of of plaques, but you're not reversing it. You're not taking that artery and making it younger, healthier. That's what we want to do is is, is take your, your artery that's that's being impinged and, and opening it back up and reversing the damage. That is the. 

Kevin Folta: No, that's really cool.

I really appreciate that last thought because you're actually dealing with the problem rather than you know, these other sort of somewhat potentially preventative measures depending on who you talk to, I guess, but where are we in terms of the pipeline of these drugs that are working to reverse this and are these something that are currently being an animal testing right now or something you've seen clinical trials?

Oki O'Connor: Yeah, so we are we're well into animal testing for for safety and from cology. We are our non [00:34:00] GLP. Safety testing is, is all very clean. The pharmacology the pharmacokinetics are all very good and favorable along expectations that we we, we wanted to see. And so we're actually moving very quickly towards towards clinic.

We've we've already had three meetings with with regulatory agencies in the UK and in the United States with FTD. So we're looking at at getting approval to, to start human clinical trials. Next year in 2023 for phase one human safety testing. 

Kevin Folta: What are some other potential applications?

You mentioned Alzheimer's disease having some sort of roles with the oxidized cholesterol what are maybe the broader implications beyond athletes squirrel? 

Oki O'Connor: Yeah. So we actually got a, a small grant from the national Institute on aging to, to look at our drug in [00:35:00] Alzheimer's disease because oxidized cholesterol is implicated in Alzheimer's disease as well.

Most people think of, you know, the debate between amyloid, beta and tau when you're talking about Alzheimer's disease and I'm not going to wait into that and I'm not an expert on it, but fundamentally. Alzheimer's disease and dementia is a part of brain aging, and there is an application of oxidized cholesterol in that process as well.

One proposed mechanism is that the microglia, which are like the macrophages of the brain and in fact they have the same root immune cell that, that creates microglia as what creates macrophages microglia are supposed to clean up the junk in. In the brain like amyloid beta plaques.

And so just like the plaques that are in the arteries that you're worried about it may be that the microglia and the brain are [00:36:00] accumulating oxidized cholesterol and losing their function and losing their ability to create. Amyloid beta plaques. Another aspect of of brain aging is a vascular dementia where the same kind of things that we're trying to treat in the in the rest of the circulatory system like in an artery leading to your heart.

That you have vessels through out your brain, of course with blood flow that can accumulate lipid and plaque just like in the rest of your body. So those are ways that we can use our existing drug in other aspects of of That caused other diseases like Alzheimer's disease and other kinds of dementia.

Yeah. In 

Kevin Folta: a way it almost seems like a very obvious target because the brains are like 20% of the body's cholesterol is in the brain. I mean, it's a huge amount. And so it seems like a really intuitive. 

Oki O'Connor: Yeah. And what's the biggest [00:37:00] genetic risk factor for Alzheimer's disease. It's the APOE E gene, right? And the APOE gene is a cholesterol transporter, and people ha it hasn't gotten nearly enough research and it's still not well understood.

Is why is your particular illness. Of April E the most predictive, it's not an Alleo of you know, something that creates Emmeline, beta or, or something related to tau. It's an oatmeal of clubs, cholesterol, metabolism and it's not well studied or understood enough yet, but clearly in my mind, cholesterol should be involved in in the.

So 

Kevin Folta: what's next for underdog aside from these drugs, which are targeting the oxidized cholesterol, what else is in the, on the white board or potentially in the. 

Oki O'Connor: Yeah, so, oh, you know, first and foremost, we're trying to get our, our first drug approved for an aspect of of [00:38:00] cardiovascular disease caused by atherosclerosis.

Secondly, we wanted to see if there's other indications, other diseases that will benefit from our, the drug but third we have this platform for. Designing cyclodextrins to bind small hydrophobic junk bio molecules that accumulate with age. So there's other Oxy sterols that are resolved from.

From free, radical damage that we can target and other things that built up in the license zone other aspects of that may be good targets. There's other things in the high Not only does oxidized cholesterol buildup in the eye and contribute to macular degeneration, but so do retinol derivatives like biz retinoids that are a result of damaged retinol which also happens to be small and hydrophobic and something that we.

I might be able to [00:39:00] to target with our technology. So th those are some examples of of things that that we were want to go over go after with with our technology. 

Kevin Folta: So where can people learn more about aging, biology, and longevity technology? 

Oki O'Connor: Yeah. So more broadly you can listen to to podcasts like this to podcasts that are that are focused on on aging itself.

You can go to to, to websites of. Of organizations like the life extension advocacy foundation their social media is is fantastic and their messaging on on aging and damage repair is great. Sens research foundation which is where my, our technology spun out of is a, is a good source.

The buck Institute on aging has a lot of great resources. I almost shouldn't be, you know, picking winners here because there's so many that I'm going to leave out so much. [00:40:00] But there's also some great books that people could read. I think books. You know, the, the, the, the most curated and and densest way to, to learn if you're not, you know, a scientist reading the primary literature and and do you want to absorb an entire field in one or a few books?

I'd recommend ending aging and ageless by Andrew Steele. The second the first biopsy degree. 

Kevin Folta: Okay, that's really helpful. And maybe maybe along that same line, it seems like this idea, especially with this, you know, big bubble than the population of baby boomers who are aging and moving into their senior years.

There seems to be a lot of people kind of taking advantage of this and maybe a lot of products that are maybe useless products, but are targeted towards this population with the idea of, you know, living longer and living healthier. And is there an easy way that somebody can help others separate the real [00:41:00] from the mythical?

Oki O'Connor: Yeah. Well, I. You need to follow the science. And even if you're not a scientist you can follow the scientists. So there's a lot of the, you know, these days, When I was starting graduate school studying aging was almost a fringe field. And now there's, there's many journals dedicated to to studying aging, to studying the biology of aging and and to study.

You know, medicine related to aging. So it's an entire field in and of itself. There's departments in groups at most universities these days. So there's a lot of scientists, professors academics, who are experts on aging, who are writing academic papers about this giving talks and Yeah.

And and working with with companies like mine. So you can you can look at at a company and you [00:42:00] can look you know, do they have scientists that are associated. With the product. Is it going through a process? You know, is it, is it is it a pharmaceutical or is it a nutraceutical? Is it if it's a nutraceutical, that means it doesn't have much or any regulatory oversight.

So what kind of. Of health claims, are they making and are they credible? And is there research to back it up? Are there scientific articles that can be referenced in the, do those scientific articles actually support what it is that the people who are selling this are claiming, so you, you can do.

Yeah, I had to say do your own research because that's become a little bit of a bad word these days. You can do your own research, but there's also a lot, a lot of scientists, hundreds of scientists these days who are experts in aging, that you can look for their opinions on these things. And you don't just have to go to.

You know, like the, the Joe [00:43:00] Rogan show or something and get a, you know, a possibly less informed opinion. There's, there's, there's a lot of great experts out there now who can have informed opinions on these things. 

Kevin Folta: Yeah. And you get in, they're actually very much in touch. I'm always amazed at the number of scientists that you can find on Twitter, who would be happy to answer your questions, or at least.

You know, the, the thing, the stuff that comes from jellyfish is a bunch of garbage, you know, and so reach out to other folks and really vet these things because there are a lot of, at the same time we have legitimate therapies coming out. There's also more and more supplements and nutraceuticals that try to fit into that same space.

And you really need to have some sophistication sorted out. I mean, even, I would say. And so it's something that, you know, I always encouraged listeners, you know, do your homework and talk to the experts and reach out to them. And is underdog, or are you I'm on Twitter or other places in social? 

Oki O'Connor: Yes, a underdog is on Twitter [00:44:00] and LinkedIn and Facebook and they can find us at underdog pharmaceuticals.com at our underdog pharmaceuticals Facebook page.

And a LinkedIn page and Twitter concept, the same name 

Kevin Folta: that works out great. And it kind of ramp things up. If you are able to solve the significant problem of cardiovascular disease related maladies, like a, you know, Affleck, sclerosis associated disease and a and stroke, what do people die? And do you have a potential therapies in the pipeline for that?

So it's kind of the old Wayne Gretzky, right? Like he's not great. Cause he skates to the puck, he skates where the puck is going to be. And can you project, you know, what would be the next major issue for us going forward? 

Oki O'Connor: Yeah. So. For one thing, there's no one, you know, magic pillar, magic drug, that's going [00:45:00] to, you know, cure heart disease or you know, completely obliterate heart disease and stroke or something like that.

And and I don't want to try to claim that that, that our drug is going to do that in one fell swoop. I think it has the potential to, to be better than than anything else and to be a huge leap forward. Isn't going to be the, be all and end all. So there's going to be a lot of hard work from a lot of researchers and a lot of clinicians and and and other companies that are going to solve this problem together.

But you bring up an interesting point, which is there's all these demographic studies that say, well, if you. Cured cancer. How many years would you add to the human lifespan or if you cured heart disease, how many would it be? And you end up with with kind of depressing numbers, like, you know, you know, two years or three years or eight years or something like that.

So you know, the you know, the question, you know, there's a sort [00:46:00] of a, Y. You know, question at the at the end of that, a few, you know, cure or the biggest disease in history, and then you only get you know, five or 10 years out of it. You know, what was the point? Well, five or 10 years is still a pretty significant percentage of the human life span.

So don't, poo-pooed that for one thing, but for another thing, these things are all synergistic and they'll add up. So. The point is that if you only tackle like one small aspect of aging, then you know, you're ignoring the rest of the problem. So if you're getting rid of oxidized cholesterol, you still need to get rid of the other toxic oxidized and You know, hydrophobic, small molecule junk that builds up and you also need to get rid of the the protein aggregates that, that built up intracellularly and extracellularly and the glucose cross-linked proteins that are everywhere in your exercise or a matrix and the senescent cells that are accumulating in in all of your replicative tissues.

[00:47:00] And so on and so on. So. You, you have to go. And one by one solve the, the different aspects of the different kinds of damage that contribute to aging. Both. If you want to cure the diseases of aging like cardiovascular disease and Alzheimer's disease and and all of the others, as well as the aging process itself.

So it it w. Ours is one piece of the puzzle. We hope to be able to contribute to a few pieces to that puzzle over the coming years. But there's a lot of hard work ahead of us. 

Kevin Folta: All. This seems like it's opening up lots of opportunities. We've got aging populations and a new emphasis on understanding the biology of senescence on human senescence and extending life and longevity.

And so if there were students or others who thought maybe this was. Fertile ground to explore further professionally, what would you advise them to do well, 

Oki O'Connor: For [00:48:00] students going through undergrad I really recommend that that they get into internship laboratory internship programs. If you want to get into science, if you want to become a biologist working on aging, I really recommend that you get into a lab at your university or get go to a.

Internship program elsewhere. I have mentored students for for over a decade through the sens foundation, summer scholars program which has been a great program for, for students to to get involved and, and to learn to become scientists There's for, for people who are in different fields or who are maybe already biologists, but haven't gotten involved in aging and want to learn more I've been a mentor for the on-deck longevity, biotech program, which is in its second class now.

And it seems like that's a really great program where I've had a lot of great conversations [00:49:00] with. With people trying to transition into the aging field. And there's a new program that I've just gotten involved in called less death.org run by a good friend of mine named Mark Hamilton.

And that is a it's starting its first its first class this summer. And it's, it's being styled as kind of a bootcamp where mark wants to bring people, engineers. Software engineers, mechanical engineers medical doctors, people from other fields and figure out how can we take your expertise? And.

Partner you with the biologists so that you can synergize your your, your your professions to help bring treatments for aging and atrial lead to disease to to reality to, to, to clinic to, you know, to medical devices, you know, faster and more efficient. Then the biologists working alone.

So those [00:50:00] are some, some ways that that people can, can get involved them. 

Kevin Folta: Okay, well, thank you so much, Dr. Okie O'Connor. I really appreciate everything that we've talked about here today. I've learned a lot and, you know, as we all kind of fight the calendar, it's good to know this kinds of stuff is going on.

So thank you very much for your time today. 

Oki O'Connor: It's been a real pleasure. Professor felt I've, I've really enjoyed myself here today. And 

Kevin Folta: as always, thank you for listening to the talking biotech podcast. We're going to be learning more and more about new technologies that expand beyond just simple biotechnology.

Thinking about novel drug design, novel problems that can be solved and how they may help the human condition as well as the environment and issues in food security. As we go into our eighth year, I appreciate everybody listening on a weekly basis. We have more downloads. Ever, and I really appreciate you take the time to listen to this podcast.

So this is collaborative talking biotech podcast, and we'll talk to you again next week.[00:51:00]