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

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
TCat
Contributor
Contributor
Posts: 52
Joined: Wed Oct 30, 2013 11:44 am

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

Postby TCat » Mon Apr 09, 2018 6:04 pm

“Using human brain cells, scientists at the Gladstone Institutes discovered the cause of -- and a potential solution for -- the primary genetic risk factor for Alzheimer's disease, a gene called apoE4.
..
In a new study published in Nature Medicine, researchers revealed how apoE4 confers its risk for Alzheimer's disease in human brain cells. What's more, they were able to erase the damage caused by apoE4 by changing it, with a small molecule, into a harmless apoE3-like version.”

https://www.sciencedaily.com/releases/2 ... 112559.htm


What do you think?

NF52
Support Team
Support Team
Posts: 1291
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Postby NF52 » Mon Apr 09, 2018 8:39 pm

Dr. Huang is very well respected as an ApoE 4 researcher, and his lab has gotten significant increases in funding. Using stem cells to create human neuron cells with Apoe 4 sounds exciting. If it leads to an actual effective treatment, which would be more than a decade away, I’m sure, he’ll probably be up for a Nobel Prize in Medicine.
He appears to have early “proof of concept”. I imagine drug companies will be glad to help bring the concept to the clinical trial stage, if possible.
Thanks for sharing!
4/4 and still an optimist!

Fiver
Senior Contributor
Senior Contributor
Posts: 597
Joined: Wed Feb 01, 2017 12:51 pm

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

Postby Fiver » Tue Apr 10, 2018 1:06 pm

Thanks for sharing! The link was broken for me so here is what I have access to now (below). Working on full text access, just came out yesterday.

This looks to be a very thorough, very useful study. They really did some fine experiments! I guess that is what gets someone published in Nature Medicine. The visualization of APOE4 problems is really no fun to look at. The hook at the end is the "small molecule corrector" for apoe4. THAT would be very interesting! I suspect once I manage access we will find that they don't reveal the compound, probably just a code of letters and numbers. But I wonder if it would be a small phenolic compound. Just a guess.

https://www.nature.com/articles/s41591-018-0004-z

Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

Fiver
Senior Contributor
Senior Contributor
Posts: 597
Joined: Wed Feb 01, 2017 12:51 pm

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

Postby Fiver » Tue Apr 10, 2018 1:27 pm

OK, given the quality of the study it was worth the $4.99 to rent the article for 2 days. I was not disappointed. The work is very good and rather convincingly shows that the risks of apoe4 come from a gain of toxic function, rather than a loss of apoe3-like function. Gene editing of cell lines from apoe4 to apo3 back to apo4 made the symptoms go away and come back - these were changes in AB levels, tau levels, and most interestingly loss of GABAergic neurons. This implies that gene editing of human apoe4 to apoe3 would resolve the problems. Also, PH002, yes that is the "structure corrector" - I was right that they were not going to tell us what it is - did an amazing job of eliminating the toxic effects of apoe4 in (as far as I can tell from a first read) all ways.

I think it is ok to include one setence from the paper "Treatment of ApoE4/4-hiPSC-derived neurons with the ApoE4 structure cor-
rector PH002 ameliorated the detrimental effects of ApoE4 on tau phosphorylation, Aβ production and GABAergic neuron
degeneration in a dose-dependent manner."

It's a bit hard to see the normal effects of apoe4 in the cells but they show two ways of correcting the problem, at least in cell lines.

Recommend a read for those interested in the study.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

Fiver
Senior Contributor
Senior Contributor
Posts: 597
Joined: Wed Feb 01, 2017 12:51 pm

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

Postby Fiver » Tue Apr 10, 2018 1:40 pm

found the PH002 molecule in a previous 2011 paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089564/

Small-molecule Structure Correctors
Two small-molecule structure correctors were used in the current study. One, GIND25, disrupts apoE4 domain interaction (Ye et al. (36)). The other is a newly identified phthalazinone derivative, 4-{4-[2-(3-methyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-acetylamino]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (PH002, Merck) that disrupts apoE4 domain interaction more potently than GIND25.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

Fiver
Senior Contributor
Senior Contributor
Posts: 597
Joined: Wed Feb 01, 2017 12:51 pm

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

Postby Fiver » Tue Apr 10, 2018 2:00 pm

If you are interested in the chemical structures. a different open access paper is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285306/
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

circular
Senior Contributor
Senior Contributor
Posts: 5072
Joined: Sun Nov 03, 2013 10:43 am

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

Postby circular » Tue Apr 10, 2018 7:19 pm

Some of us have given blood to E-Scape Bio to work on this approach pursuant to Huang’s work. You can search the forum for it. I’m not sure if they need more volunteers.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

Fiver
Senior Contributor
Senior Contributor
Posts: 597
Joined: Wed Feb 01, 2017 12:51 pm

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

Postby Fiver » Wed Apr 11, 2018 6:46 am

Thanks circular. I was just reading their webpage. It's so hard to keep up with all the studies. Perhaps some forum members have cell lines like those used in this study. That would be a real contribution.

This article is really impressive - the amount of time and effort to put together something like this must be amazing.

I have not been able to find an explanation for why the PH002 compound is not a useful drug. I presume it doesn't pass the BBB or is toxic, and E-Scape Bio is developing a library of similar lead compounds for testing. Do you know why PH002 itself isn't a therapy?
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

User avatar
LG1
Senior Contributor
Senior Contributor
Posts: 360
Joined: Fri Dec 18, 2015 10:32 am
Location: Dallas, TX

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

Postby LG1 » Wed Apr 11, 2018 10:53 am

circular wrote:Some of us have given blood to E-Scape Bio to work on this approach pursuant to Huang’s work. You can search the forum for it. I’m not sure if they need more volunteers.

I also participated in the Escape Bio study (gave blood sample) It must be a different study from the same researcher using skin cells? Dr. Huang is definitely one to follow, seems like very exciting news!
Last edited by LG1 on Wed Apr 11, 2018 11:33 am, edited 1 time in total.
ε4/ε4

circular
Senior Contributor
Senior Contributor
Posts: 5072
Joined: Sun Nov 03, 2013 10:43 am

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

Postby circular » Wed Apr 11, 2018 11:03 am

Tom wrote:Thanks circular... Do you know why PH002 itself isn't a therapy?

Sorry, I know nada.
ApoE 3/4 > Thanks in advance for any responses made to my posts.


Return to “Science and Research”

Who is online

Users browsing this forum: No registered users and 11 guests