Researchers found that ATDR alone isn't the active signal, it's a precursor that neurons further convert into ATDRA, the acidic form of the vitamin A derivative. ATDRA turned out to be a selective activator of RXR-gamma, solving the targeting problem that had doomed earlier drugs which hit RXR receptors too broadly. When tested in mice, both ATDR and ATDRA reduced myelin damage from low-oxygen exposure, and in a standard autoimmune mouse model of MS-like lesions, giving mice ATDR alone was enough to significantly increase myelin volume and reactivate the stalled repair process.
- 01
The earlier failed drug referenced for comparison was Bexarotene, which activated RXR receptors non-selectively across the body rather than just RXR-gamma.
- 02
The MS-like mouse model used is called experimental autoimmune encephalomyelitis (EAE), a standard model that mimics MS pathology.
- 03
ATDR is highlighted as easier to manufacture than ATDRA, and since neurons can convert ATDR into the active ATDRA themselves, delivering the simpler precursor is sufficient.
1,000 words · auto-generated from the episode video
1:17:17remember the ATDR is the stuff that came out of the red stat right it's the control even makes the red >> stat the control even makes the ATDR if I add that to my OPC's then all of a sudden I get this effect >> okay >> so there is something else >> this proves that ATDR is just a precursor >> Mhm. And the neurons are doing something else with that ATDR. Right. >> Yeah. Yeah. Yeah. Okay. >> So, not only am I getting more of ATDR, but the neurons are doing something more with that more ATDR is. So, it's almost like it's a it is a um just by having the neurons need it's a it's a fundamental uh ingredient for whatever it is the neurons are doing, but it is
1:17:58not the solution in and of itself. >> Yes. And one of the inclinations that these guys had, one of the inclinations that these guys had was, well, the ATDR, which is um a second, you know, it's a version two of vitamin A of the retinol. There's a version three, which is ATDR A, it's just ATDR with an acid. Okay. It's the acidic version of that that maybe this thing is maturing into. >> Ah, >> okay. >> Okay. >> When they add that, >> they get a massive spike. >> They get a massive spike. So all of those columns are all of the different permutations and combinations of what I could add >> to my to my cells. They were like okay look I don't know
1:18:38>> yes >> what what's going on let's just do all of the permutations and combinations and if you look at the fifth column >> y >> you can see a bunch of mileelination happening >> that is with ATDR alone with the acidic version of this >> so when we introduced the ATDR >> the acidic version we are seeing things things happen now >> and so we were the ATDR base was directionally helpful >> and it's just like it's like a a slightly It's a diff slightly different permutation >> of it. >> Yes. And and the key insight here and that's that's effectively the punch line is this ATDRA this acidic version of the vitamin A derivative.
1:19:21>> Mhm. >> That is the selective activator of the RXR gamma. >> Bingo. >> Right. >> Bingo. >> The the the failed trial. >> The beexotin from earlier. >> Yes. the beexa protein from earlier that was not only targeting gamma but also targeting everything. >> Yes. >> Now we've got a selective activator that is going to target only the gamma >> and and so and what's so this is perfect because from from earlier when we talked about we were we had identified the uh RXR as like the where we needed to target >> that that's what we got to >> do for the therapeutic but we couldn't target it selectively enough. We've figured out the size problem for delivery. We did not figure out the
1:20:02targeting problem. The ATDR is the solution to the targeting problem we defined earlier in the show. >> Yeah, exactly. And so, how do we make sure right the and this is where we get in the translational payoff of the entire study, right? We we've established the science. >> Yes. >> Now, can this actually work as something that >> perhaps could combat MS and maybe even reverse the effects? >> Can we deliver the actual solution? >> Yeah. So they they got young mice, they exposed them to low oxygen and then those young mice received in injections of ATDR and ATDRA. Both molecules actually reduced that impact of hypoxia.
1:20:44>> Okay, so both molecules actually worked. It makes sense because uh a mouse brain has neurons. It got the ATDR which it wasn't getting earlier because I mean this is in control remember. Okay, this is in control that don't have that mutation. So, this is normal mice, but we're giving them the stuff that the mutation makes. >> Yes. >> And it's working. >> You're getting remination. >> Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. >> Okay. >> Oh my goodness. >> And the the the killer is really the next one. >> Yes. >> The next one is so because this was this was hypoxia. >> Mhm. >> Now, what if we straight up go in lession? >> Right. which are the two this >> because hypoxia I don't know it could be
1:21:24doing other things >> right right >> what if we now normal normal environment but we go ahead and we do a lesion um do we get like with in an MS- like brain there are these things called um autoimmune ancilitis E AE these types of mice are basically a standard model for multiple sclerosis because they mimic a lot of the a lot of the effects and there you can see the control has not that much myelin But the ones that get ATDR, this particular type of mouse brand that mimics MS, if you give it ATDR, you don't have to give it ATD, just even ATDR, which is way simpler to make,
1:22:05actually. >> You're getting a lot more mileelination. The mileination volume is increased, which is what we want to see. >> The repair process is is reactivating. It's becoming successful again. This is so so and so now we've we've we've weaved this story >> which is so so good >> to this point where we've now understood the current state of play with MS what the limiting factors were for delivering a therapeutic which was being able to target target this RXR gamma. >> Yep. >> Um we knew we we needed to target RXR but we couldn't selectively do so. >> Yeah. Cuz it was going everywhere. We
1:22:46found this other pathway through looking at the evolutionary uh
Evolutionary BiologyNeurobiologyPharmacologyRegenerative Medicine