Vitamin A is converted in the body into retinoic acid, which acts as a transcription factor by binding to RXR receptors. The oligodendrocyte precursor cells that build myelin specifically use the RXR-gamma subtype, and knocking out that receptor in mice eliminates their ability to remyelinate axons. A clinical trial in Cambridge, UK tested a drug called Bexarotene designed to activate RXR-gamma and successfully crossed the blood-brain barrier, but it also activated the RXR-alpha and RXR-beta subtypes found in the liver and kidneys, causing hypothyroidism and, in 90% of patients, dangerously high blood triglycerides. This showed that the original blood-brain barrier delivery problem had been solved, but a new problem of receptor targeting specificity had taken its place.
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Vitamin A is normally consumed as beta carotene rather than retinol itself, since the body can regulate how much is converted, whereas direct retinol exposure, such as from some skincare products, is dangerous during pregnancy.
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The original blood-brain barrier obstacle was that monoclonal antibodies were too large to cross it, prompting researchers to design smaller molecules like Bexarotene instead.
1,582 words · auto-generated from the episode video
38:15bloodb brain barrier, what do we need to do? We need to make our thingy smaller. >> Okay? Because the bloodb brain barrier has extremely tiny holes. And if I can get through that hole, then perhaps I can get into the neurons, get into the astroytes, get into these oligodendrites and help out where I'm trying to help out. So researchers have started turning to small molecule drugs but these molecules are tiny and they're lipopilic meaning they are fat soluble. Lipophilic meaning fat loving so they slip past the blood bloodb brain barrier but they're also going to slip past every other barrier. >> Yeah. >> Right. So we want target specificity.
38:56That's not going to happen for a lot of these chemicals. >> So this is like almost it's the problem in the opposite direction. >> Yes. because now I'm slipping through the blood brain barrier, but because I have to be so small to get through that, I'm also getting it to the liver. I'm going to get to the kidneys. I'm going to get all over the place. And one of the big most catastrophic and educational failures in this case was the trial of Beexa Rotine. So, Beexin was an FDA approved oral medication that was targeting something called the retinoid X receptors, which you see over here, the RXRS. These retinoid X receptors are nuclear transcription factors. We've talked about
39:36transcription factors a lot. These are the onoff switches for a bunch of genes. So if you can target the transcription factor, then you can influence what types of genes the cell is actually getting access to. And there you see a bit of DNA. And the transcription factor is the protein that goes in and locks in on that p piece of DNA recruits for example RNA polymerase to make RNA that makes the protein that actually makes whatever thing that is happening. But if you can target this thing then perhaps you can actually have a control of the on andoff switch for something that controls whether the stem cell goes on to become a milein. That's the idea. >> So we're going back to the factory and the instructions of how the factory
40:17generates its stuff with the right instructions. It's like maybe let's just reprogram at to at the factory to factory settings. >> Exactly. It's like maybe the factory has some instructions and I'm just going to black out. >> Yeah. >> Right. I'm going to like redact a bunch of instructions. The problem is the redaction is going to happen over all the instructions because it's not specific. >> That's the idea that I'm trying to get to >> because of this the size problem we talked about earlier. And so it's going to effectively start turning off. It's going to start impacting functionality that you were not trying to change. >> Yeah. Yeah. because it can't be specific. >> Exactly. Yes. Because it can't be specific because it's so small. Now, um before we get into the details of that failure, >> um a brief
40:58a brief sojourn into vitamin A because that's going to be important later on in this episode. Vitamin A is very important and that RXR is very much tied to that vitamin A. The that transcription factor is very much tied to the vitamin A. So vitamin A is a broad broad family of fats soluble molecules like retinol is one specific molecule that belongs to that and these retinoids are critical for neuro development. Too much and it's bad, too little and it's bad. That's why a lot of these prenatal vitamins have vitamin A. Um but they have it in the form of betaarotene and not like straight up vitamin A because betaarotene our body can then process and then it can decide how much vitamin A to get. If you just
41:40straight up inject yourself with retinol, that's really bad. And that's why like the skinincare products that have retinol is bad during pregnancy because then that goes into the infant and then that that's going to cause trouble. >> So um the active form is something called retinoic acid and that acts as the transcription factor for these for these um receptors. >> Yes. >> Okay. >> Right. >> So and that regulates the gene expression later on. >> Right. Now, pre-clinical studies showed that these pregentor cells, the stem cells that go on to become the myelin, >> the OPC's, >> yes, those guys, they express these RXRs, the um the the the
42:24receptors, but only a gamma kind. Okay, there's there's multiple types. And the stem cells in the brain that become myelin, they express the gamma kind of the receptor. Okay. >> Okay. And then when researchers knocked out that gamma kind then the mice lost all the ability to reminate the axons. So now we have a better idea of the specific receptors necessary that that the OPC's use cuz there's a lot of options on the table. And so part of maybe what was happening before was we weren't choosing the right flavor. >> Yes. >> And now we know we we were making lemon pepper when we needed to be making uh teriyak. >> Yeah. So at least we now know that we
43:04got to make the gamma, we got to make the teriyak, right? And so >> this um clinical trial in Cambridge in the UK decided that be um beexa, what is it? Beexa protein, sorry, I'm really bad with these medical terminologies to be honest, but beexin was something that could target the gamma receptor >> and then perhaps reinvigorate the stem cell differentiation from stem cell to myelin. The problem turns out that there are other types of receptors. There is the RXR gamma which is in the brain that does the myelin stuff, but there's also RXR alpha, RXR beta, and those are in the liver and in the kidneys. And this
43:45thing was going around and targeting everything. So all of a sudden the patients got hypothyroidism. 90% of the patients developed dangerously high levels of fat circulating in the blood. Something called hypertlymia. >> This is the Yeah. And so this is so just to uh double click on this the beexotin which was this potential therapeutic right that we were going to use um did activate uh RXR gamma which is the one we know >> that the OPC's use to to basically get to this point where they can reminate. The problem is it didn't only reactivate RXR gamma. It reactivated RXR gamma as
44:27well as the alpha and beta. >> And so the all three subtypes were being activated by this therapeutic and as such it was effectively not targeted enough for the specific solution we were looking for even though we solved the delivery problem of getting through the bloodb brain barrier which was the initial challenge. >> Yeah, that was the initial challenge. Okay, the monoconal antibbody is too big. It's not going to get through. Let's make the thing smaller. Well, now it's getting through everywhere. >> Right. >> Right. >> And targeting too many things. >> Exactly. >> So, we've solved the delivery mechanism. We've not solved the targeting problem. >> Yes. And there is the challenge. How do we find a molecule that is small enough to cross the bloodb brain barrier, >> but it only activates the gamma receptor
45:09of these stem cells and it doesn't trigger some random catastrophic activity elsewhere in the body. I want to just really briefly talk about how important it is to have done this journey because we've now set the table of like where the problem set exists exactly >> today as these research teams are looking at this problem like why is this so pernicious? Why is it so difficult to solve? >> Well, we first had to identify >> the the mechanisms and the mechanics of what was actually happening. Yeah. >> Once we've identified what's actually happening, then we have to think about different angles of attack to solve the problem. Where in that chain do we go? >> Yeah. >> Right. And so then we decided, okay, let's try to see if we can reinvigorate
45:50these OPCs, which seems to be breaking down. >> Yeah. >> And then we have to get to the location. So that was the hardest problem at first cuz it doesn't matter what we think if we can't get there. >> Yeah. Yeah. Yeah. Let's get past security, >> right? Right. We got to get through TSA and then we'll figure out if we can get on the plane. So we got past security, but our ticket didn't get us on the right plane. >> Yeah. No, it's every single plane. >> It's every it gets us on every plane. And we we we're trying to go from London to Paris and so we need to get the London to Paris. Exactly. >> And so that's where we are. >> Yeah. >> Right now as we >> sort of transition into this current paper, >> right? >> This is the problem set. This is where we are. And now let's talk about where this current paper comes in. This current paper introduces the the this
46:33this current paper basically introduces the idea of evolutionary medicine into this fray. Okay. Okay. Evolutionary
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