Erasing the damage caused by apoE4 in human genes? New study by Gladstone Institutes

[antimatter37]

Was able to pull the full article and read it over. I agree with others that this work does a very thorough job of explaining the detrimental role of APOE4 in human neurons. It reads like a horror story in that regard!

The small molecule structure corrector for APOE4, ph002, is a real curiosity, also pointed out by others. It has been around since 2011, and you can actually purchase if from many different sources for about $220 per 10 mg. For some reason, however, it does not appear to have ever made it into any sort of clinical trial. You might think that if Merck, who helped develop this compound, thought there was any possibility of profit with this compound would have pursued some sort of trial given its purported benefits for AD.

This (ph002) and several other small molecule structure correctors have been around for many years now, with essentially zero positive results for actual living humans. Is it possible that when you chemically attach one molecule (structure corrector) to another molecule such as APOE4 that has functional interactions with over 1500 genetic locations in the human body, you simply cannot expect anything other than potentially massive and potentially dangerous side effects? I am not an expert in any of these areas, so this is just speculation on my part.

[circular]

Is it possible that when you chemically attach one molecule (structure corrector) to another molecule such as APOE4 that has functional interactions with over 1500 genetic locations in the human body, you simply cannot expect anything other than potentially massive and potentially dangerous side effects? I am not an expert in any of these areas, so this is just speculation on my part.

I'm trying to figure out how a structure corrector could be kept from altering other non apoe4 molecules, causing adverse affects in unrelated areas? Is there some way they can make a corrector molecule only seek and attach to apoe4 proteins? Sorry I don't have time to read the paper, and frankly now I'm not sure I want to. Enough stress without the detailed horror story part

[Orangeblossom]

I'm a bit confused about the APOE4 causing damage in neurons / being introduced into neutrons part, as

"ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors,"

https://en.wikipedia.org/wiki/Apolipoprotein_E

So would it have the same effect in general in brains as found here, considering that it is not produced in neutrons?

[Harrison]

Is it possible that when you chemically attach one molecule (structure corrector) to another molecule such as APOE4 that has functional interactions with over 1500 genetic locations in the human body, you simply cannot expect anything other than potentially massive and potentially dangerous side effects? I am not an expert in any of these areas, so this is just speculation on my part.

If their drug changes apoE4 to be apoE3-like and nothing else (we'll get to that in a second), this might not be a problem. The drug also has to get to the brain which is easier said than done.

I'm trying to figure out how a structure corrector could be kept from altering other non apoe4 molecules, causing adverse affects in unrelated areas? Is there some way they can make a corrector molecule only seek and attach to apoe4 proteins?

This is essentially the challenge of drug discovery. Every small molecule drug interacts with something other than it's target. The big question is how much drug you need to get the effect you want vs. how much drug has effect you don't want. To make an extremely simplfied example, let's say a person needs to take 10mg of drug to get enough into the brain to correct apoE4. But that same drug also binds to a different protein that causes toxicity, and you only need 5mg to get that effect. Chemists engineer this to try and get a separation between the effect they want and the effect they don't. If PH-002 was not toxic to mice, I think we would have seen a study by now.

I'm a bit confused about the APOE4 causing damage in neurons / being introduced into neutrons part, as
"ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors,"

This has always been a controversial piece of the Gladstone work. Everyone agrees that the majority of apoE comes from astrocytes. The Gladstone scientists believe that neurons make their own apoE but many other scientists disagree. The neurons in the paper were stressed, because just sitting in a petri dish instead of being in tissue with a blood supply, etc is stressful. How much this represents the actual situation in the brain has been a matter of debate.

[Orangeblossom]

Harrison- interesting. Thanks for explaining. In terms of how bad the impact seemed to be of the APOE4 in the neurons, I find this a little bit reassuring. However obviously this may impact on how the solution works in practice. Other studies have shown increased levels of APOE4 are better, in general so it may not be as simple and also about a loss of function in terms of lower levels of APOE in general. It will be interesting to see what the study yields in future.

[Julie G]

Great discussion. I've also found it a bit odd and disconcerting that human trials haven't started yet. A group of us had the opportunity to meet with Drs. Mahley & Huang, as well as Leon Chen (with OrbiMed) several years ago. Back then, they were fairly optimistic that this pharma would be available relatively soon. Something, not funding, seems to be slowing down the process .

[julespaps]

Really interesting thank you for sharing. This for me is a real positive let's hope it advances further. I see you can buy PH002 from Merck and they indeed sell it as a APOE4 modulator. Can they actually sell it as that as this is in the early stages of testing.

Another thing on my mind is that as APOE4's are we all trying to change the way the gene works in our bodies already? What I am getting at is if this did advance and in 10 years time there is a viable product would it hopefully aid all the hard work we have been doing in changing our lifestyle factors. We should hopefully still be fit and healthy, right?

Sent from my SM-G950F using Tapatalk

[cdamaden]

My questions about this are, what about all those E3/E3 people who develop AD? E4 status is not the sole contributor, and as already mentioned do we know that E4s who live an ancestral (active, sunshine, natural foods, etc.) lifestyle have an increased risk for AD? Sort of like Chris Kresser's question about surgery on your foot instead of just removing the pebble in your shoe.

[Orangeblossom]

I seem to remember from reading that neurons can produce APOE under stress? Would have to check though.

Yes, it says here

"It (APOE) is synthesized by astrocytes and, to a lesser extent, by microglia, oligodendrocytes, and ependymal cells. Under pathological conditions, apoE is also synthesized by neurons."

I wonder exactly what that means. Interesting that it also mentions

"Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms."

It is a mouse study though. People may know more on this, it's basically one of the first things I found on looking.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913361/

I know mice are different. But if this is the case could it be that the astrocytic APOE4 is protective and the neuronal APOE4 is not, and as they are only studying the neuronal one they might be missing something important?

This seems relevant as well- it also says about APOE in neurons in humans as well

"The cellular origin of apoE appears to influence its effects on AD pathology. Astrocyte-derived apoE3 and apoE4 have different effects on the production, deposition, and clearance of amyloid β (17-20, 48, 49) and on cholesterol efflux (50, 51). Neuron-derived apoE3 and apoE4 differ in their susceptibility to proteolysis (28, 30) and in their effects on tau phosphorylation (27, 28, 30, 52), lysosomal leakage (53), neurodegeneration (54, 55), androgen receptor deficiency (56), and cognitive decline (56-58). Thus, a better understanding of the regulation of neuronal production of apoE is important for unraveling the mechanisms underlying apoE4-related neurodegenerative disorders."

http://www.jbc.org/content/279/5/3862.full

So, if this only happens under stress would it not therefore be important to look at that process and what is normally happening in humans brains to cause such stress if this then leads to the neurons producing APOE4 and causing such damage? And possibly altering that...

I wonder if low APOE levels lead to the neurons producing it. That would tie in with E4s having lower levels in the first place.

[Fiver]

Great discussion.

I find the gene editting of cells in cimtire to be, well, pretty amazing.

But I think in the end the cell cultures are just a screening tool. Previous papers describe how they screned 20,000 potential drugs by computer modeling and tested the top 60 in the lab. PH002 was the best. The previous papers show that they have an amazing understanding of what shapes are important for the molecules and, no doubt, the E-Scape Bio company is building a library of other lead compounds. Chem supply companies will sell it to researchers for study. But I presume it must be toxic or not pass the BBB or something, else it would be in clinical trials, right? It does look a bit too large to pass the BBB, but that's a guess. I've tried but can't find any mention of why is doesn't work in vivo - but nothing so far.

PS - I learn a heck of a lot from ya'll!