The chapter explains why two major drug strategies for rebuilding myelin have failed. Monoclonal antibodies are too large to cross the blood brain barrier, so they worked in some mouse models but failed in human phase two trials. Small molecule drugs are lipophilic and small enough to cross the barrier, but that same property means they hit tissues throughout the body, not just the target cells, so they lack specificity. Bexarotene, an FDA approved oral drug targeting the RXR transcription factor, is cited as a major example of this specificity failure.
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RXR transcription factors are described as on-off switches that control which genes a cell can access, including genes that might push stem cells toward becoming myelin-producing cells.
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Vitamin A and retinoids like retinol are introduced as tied to RXR signaling, setting up their relevance to remyelination discussed later.
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Too much or too little retinoid signaling during neurodevelopment is described as harmful, which is why prenatal vitamins contain vitamin A.
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35:30cannot fix. These are called disease modifying therapies, DMTs. Not to be >> not that DMT. >> Not that DMT, guys. Uh this is not the Joe Rogan podcast. Um but once an axon is deminisinated these disease modifying therapies cannot force the body to reminonate it but they can perhaps force the body to stop the degradation. >> Okay. >> Stop to stop the bleeding effectively. >> Yeah. And by the 2000s the field had identified like a bunch of different signals. There's like thyroid hormone retinoids. Um but translating this into therapies proved kind of difficult. A big obstacle is the bloodb brain barrier. Mhm. >> This is something that we we revisit a
36:12lot on this podcast. The bloodb brain barrier is an essential barrier between the blood and the brain because the human brain is protected by this thing. It's a highly selective semi-permeable border of endothelial cells. Endothelial cells are just, you know, cells on the lining of blood vessels, but very specific types of endothelial cells. and they prevent circulating blood from just freely mixing with the brain. Everywhere else it's fine, but the brain is a finicky thing. The neurons are a finicky thing. And so they want a very particular environment to actually do all of the computation that we know and
36:53love. This barrier has doomed a lot of different therapies. Okay, one of the most famous was this therapy from Biogen, which I Biogen is a company. They were developing this therapy called opposumab. >> I love the pharmaceutical namings of stuff. >> Yeah, I I opposumab. Okay. Um it was developed as a monoconal antibbody that was going to target and block something called lingo 1, which is a protein that would inhibit this differentiation. So the the idea is you've got the stem cell, the stem cell is differentiating. There's a protein called lingo one that would stop that differentiation. that
37:35would stop these workers. So this monoconal antibbody is going to go attack that protein. So then the pro the workers are kind of free to >> to to do whatever. >> Yes. >> Works in mice. Human phase 2 trials huge failure because these monoconal antibodies are massive. They're complex protein structures and because of their sheer size, they couldn't actually get through the bloodb brain barrier. >> Right? In mice, the mice have a different bloodb brain barrier. So perhaps it got through. This is going to come back later when we put an asterisk on the current paper. But I still think this current paper is cool because of all the methodology. So to bypass the
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