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E4: why no urgent push for structure correctors, gene editting?

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Julie G
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Julie G » Thu Jun 28, 2018 4:54 am

Orange, with your extraordinarily high HDL, my guess is that you have some protective ABCA1 genes. The two you listed are several of many that influence HDL/apoE lipidation. If you've done 23andMe, click on the ABCA1 gene (in the browse raw data tool) and you'll see all of the various snips at play. Fun rabbit hole to explore each ;).
One would want to increase lipidation of ApoE4, decrease apoE4 levels (preferentially non-lipidated apoE4), or alter apoE4 so that it could be more lipidated, or less toxic (Wang et al, 2018). I don't think these approaches need to be mutually exclusive either.

The holy grail! I like this, Harrison. If you've figured out a "home brew", let us know. For me, it keeps coming down to peripheral apoE levels because that's something we can actually measure. Do we know anything definitive about the correlation between peripheral and cerebral apoE? I keep coming back to Rasmussen's and Goodenowe's work. Higher levels of plasma APOE are correlated with better cognition. Goodenowe has found that High HDL/low TG is a good proxy. It's telling (to me at least) that this combo is also associated with cardio and neuroprotection. I'd be hesitant to actively work on lowering HDL.

Fiver, congrats on your biomarker improvements! Please share if you'd like. I assume you've seen this paper re. lipoproteins in the brain. The working theory that I see many researchers toss around is that lipophilic statins are more likely to negatively affect brain apoE levels; whereas hydrophilic shouldn't. I don't know that we have any definitive proof.

Brian, please share any updates you have on E-ScapeBio. I continue to hold out hope, but they are years past Dr. Mahley and Huang's projected release.

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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Orangeblossom » Thu Jun 28, 2018 6:32 am

Hi yes there are others, - and some which seem to be higher magnitude than the previously mentioned, for example I have got a variant this one

https://www.snpedia.com/index.php/rs4149268

and this https://www.snpedia.com/index.php/rs4149274

Also these is a mention of this on promethease, and I've got the G for the middle one...it seems complex

rs2297404, rs2230808, and rs2020927 haplotype (CAC) was more prevalent in the Alzheimer's disease group (0.323 in AD vs. 0.202 in control); while haplotype1 (TGG) was over-represented in the healthy controls (0.595 in control vs. 0.493 in AD) ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. ABCA1 polymorphisms and Alzheimer's disease. Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms.

I noticed this on Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms.https://www.ncbi.nlm.nih.gov/pubmed/174 ... t=Abstract

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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Fiver » Thu Jun 28, 2018 7:52 am

Thanks everyone. It really helps to be able to talk through all these confusing studies.

I agree with this summary too: One would want to increase lipidation of ApoE4, decrease apoE4 levels (preferentially non-lipidated apoE4), or alter apoE4 so that it could be more lipidated, or less toxic (Wang et al, 2018). I don't think these approaches need to be mutually exclusive either.


I suspect that the E-Scape Bio folks and the PH-001 compounds (and similar) must have not themselves been good drug candidates. And, I assume, they are looking for similar candidates to screen. I found a few papers from other labs suggesting that plant natural products like polyphenols might have a somewhat similar effect, but I was less than convinced.

Julie - I did actually read something yesterday about general circulation and CNS apoe levels "going in opposite directions"....so many papers, I will look for the quote again.

A few asked about my results. I don't have all the papers here. But here is a summary, for what it is worth.

I've had poor lipid numbers for at least ten years - the typical pattern B thing. LDL and TGs always ran borderline high, my HDL started out at 29 about ten years ago, I have a family history of CVD (some at young ages). My cardiologist had me try niacin (1g, then 2g) but numbers barley improved. HDL went "up" to 31 and the particle size pattern improved some. Not very exciting. I was already exercising a lot - running, lifting - mostly as stress relief. I was 6'0" 170-178 lbs during this time. I began having strange symptoms, on and off, that were neurological things - just worrying. I was tested for MS. Ultimately, I was told it was just stress....a very unsatisfying answer....but, sure, I had some stress.

Turns out my vitamin D level was 9!

So I added a vitamin D supplement. Fish oil (2x1g capsules / day). Tumeric 400mg. And I slowly began trying out a pre-ReCODE program in the past few years, as I tried to get my mom on the plan.

In January I had phased in a real ketoflex type diet with 1 hour overnight fasting. I lost ~13 pounds in maybe 4 weeks and it has stayed "lost". I focused on lowering carbs and, as a result, I was probably getting more saturated fats than is ideal. In January I got a large number of labs and consulted a FM doctor.

LDL, TGs, and other "negative" lipid numbers were all up, way up, even compared to my already existing pattern-B. HDL was "up" to the mid-30s.

Tests showed I had a wheat gluten allergy I wasn't aware of. Some indications of inflammation in vessel linings, a high PLA-2. And low levels of some steroid hormones that would have required some sort of replacement therapy. The working hypothesis was a "pregnenolone steal" sort of situation where a stress response was stealing away steroid skeletons for cortisol production, reducing levels of other steroids.

* later I would learn that niacin treatment raises PLA-2 biomarker, making it seem like there is more inflammation than there actually is.....hmmmmm.....

5000 IU of Vitamin D got my levels up to 40, still not where FM doctor (or Dr. Bredesen) would want it.

So I had to make some decisions. For various reasons I opted not to work with the FM doctor at this time. I made my open-minded research-savy cardiologist my go-to doctor and kind of took control.

I researched the statin question and, for me, decided it was necessary. Started with mid-level rouvastatin, then switched to the older, slightly less powerful atorvastatin specifically because it was more lipophillic and more likely to reach the brain. I know, easy to argue either side of this one. But I was convinced by some large studies showing benefits, and papers indicating that potential side effects like "brain fog" are unrelated to AD. I'm on 40mg atorvastatin - the high dose. I do get a little "fuzzy" sometimes, like for 1-4 hours after taking it. So I take it at night.

I added: B vitamins (I alternate between the methylated (Life Extension's "homocysteine resist") and regular formulations), ACAR and ALA, 470mg Aswagandha. Took some NR and quercitin for a while too.

For 5 months I cut out wheat (all breads for example) and kept carbs low. I learned to like, then really NOT like, avacados. I set a lower weight limit, and when I reached that weight I relaxed my diet. I found I can relax carbs from 30g max (January-February), to 60g max (spring), to having the occasional slice of pizza so my family doesn't think I'm totally no fun...and it seems ok.

Anyway, my June numbers after being on a "half reCODE" plan in 2016-17 and getting serious in January 2018....so 6-7 months on this newer plan:

TGs 69
total CHO: 104
HDL: 38 (highest it has ever been)
LDL: 52
CRP: 0.21 (normal range (0-3) mg/L
vitamin D: 72
total T: doubled, now in mid normal range.
all other numbers: normal

Very pleased. It seems the ketoflex diet and the statin work well together. Vitamin D is good, inflammation seems down, and my total T is now normal (surprising since statins usually lower T about 5-10%). I think the statin obviously had a huge effect on the blood work, though I'd like to think the exercise and diet helped too.

Of course, absolutely none of this tell me what is going on inside my head.
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby LG1 » Sat Jun 30, 2018 11:18 am

Fiver wrote:................

So I've been paying special attention to studies I find showing that good things seem to come from (a) reducing apoe4 levels, (b) "correcting" apoe4 structure to be "E3-like" using small molecules, and (c) what seems like the futuristic approach to gene edit apoe4 to apoe3 in humans one day.

I know these studies have been discussed. I'm just wondering....is there some debate that apoe4 isn't the root cause of most instances of LOAD? Is there some really intensive effort out there that I'm not aware of? Is it all hush-hush secret R&D at biotech firms? Is it hard to find volunteers? In short, why no public aggressive international push to somehow "correct" e4....one that seems proportional to the scale of the problem? What's slowing things down?

Thanks for thoughts. I'm learning along with everyone else.


It's great to see this question on the forum. I have been a little confused as well about the lack of excitement equaling mine for this specific study. We have a lot of brilliant members on here. Part of me figures if they aren't excited I shouldn't be. The rest feels that Dr. Huang's research with gene editing is Huge and exactly where the focus should be.

Have you looked into his current/upcoming studies? Here is the link to his profile page on UCSF's site listing all the studies he is heading right now: https://profiles.ucsf.edu/yadong.huang The one involving CRISPR/Cas9-mediated gene editing is my favorite but all of them are worth a look. You might/might not notice but the list is scrollable and includes his past projects as well.

Wish these things didn't take so long. Wondering what, if anything, they are doing with this in China, the UK etc..?
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Stavia » Sat Jun 30, 2018 10:18 pm

LG, I'm very very wary of unforseen, unexpected effects of new biological agents. I am watching this with moderate interest. I believe its premature to expect scalable, useable therapy before... maybe a decade?

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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Fiver » Sun Jul 01, 2018 7:59 pm

I agree with Stavia. This really seems to be a good direction. But the gene editing has several hurdles - it has to work, work inside the brain, be accepted by agency and society, and become affordable and covered in the insurance framework. The small molecule apoE4 "structure correcters" not only have to work on the molecule and be non-toxic but also to enter the brain and probably the internal transport bubbles of the neurons. That's tough.

I do think it will happen. Maybe in a decade, like Stavia said.

I just saw this and understand that there is a section about "apoe4 gene therapy". Will watch tomorrow.

https://www.cnn.com/videos/health/2018/ ... ps-change/
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Brian4 » Mon Jul 02, 2018 3:58 am

Hi everyone,

We have two exciting new developments put together in one thread here. About the time-scale question, I think it's quite different for each.

I think the small molecule correctors will probably enter Phase I trials within 2–3 years, and, if things go well, could progress quickly from there.

But I think gene-editing to correct the APOE gene in a safe, effective way will take much, much longer.

I just got back from ISSCR, and learned a lot about research priorities connected to gene-editing. Researchers attack low-hanging fruit, for mostly obvious reasons (need to show progress to get more grants, or to get tenure, etc.). Within the realm of neurology, gene-editing work is mostly focused on diseases that affect a delimited part of the brain. The idea is to remove the patient's own cells, correct the gene in a dish, and then return the corrected cells back into the relevant part of the brain. This approach has already shown progress in laboratory animal models of Parkinson's.

With APOE-ε4, this approach will not work, because it's basically all the cells in the brain that would need to be corrected. (Correcting only cells in the hippocampus, or progenitor cells, would be one approach that might help reduce the risk of AD per se, but not the risk of other types of dementia for which we're at increased risk.)

For us, we would need an approach that gets the editing tools to circulate throughout the brain long enough to correct nearly all of the cells in the brain, and safely. In a dish, one can sort the cells to remove the ones that were "off-target edited" before returning to the brain. Not so with the non-dish approach needed for us.

If researchers made correction of APOE-ε4 a priority, it could happen soon. Maybe we could start a separate fund to create a grant for research into that specific goal?

Otherwise, I'm much more hopeful about the small molecule correctors.

Brian

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Re: E4: why no urgent push for structure correctors, gene editting?

Postby LG1 » Mon Jul 02, 2018 11:44 am

I understand, I should be more specific. Gene editing is CRSPR and this is not, although Dr. Huang is using that tech in some of his current studies.

The next step for Dr. Huang, the improvement of the structure corrector compounds that 'fix' the Apoe4 protein is most promising! For anyone curious that hasn't come across it, this is the article recently making the rounds of the internet that discuss his Gladstone study that I find so exciting. https://www.technologynetworks.com/neuroscience/news/small-molecule-structure-corrector-fixes-genetic-risk-factor-for-alzheimers-disease-299525
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby LG1 » Mon Jul 02, 2018 11:52 am

Stavia wrote:LG, I'm very very wary of unforseen, unexpected effects of new biological agents. I am watching this with moderate interest. I believe its premature to expect scalable, useable therapy before... maybe a decade?

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Decades away :(

CRSPR is both scary and potentially awesome. Minus the potential social implications I am just super interested in the science.

I hope Brian4 is right and the structure corrector tech is going full steam ahead!
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Re: E4: why no urgent push for structure correctors, gene editting?

Postby Brian4 » Tue Jul 03, 2018 6:17 am

LG1, for the record, I totally see why Fiver put these two topics together. They both share the quality of seeming like potential outright cures for most dementias, once one realizes how much of LOAD and other dementias (to say nothing of heart disease, and so on) is the result of APOE-ε4–related pathology. And hence the question: Why no urgent push? Why aren't people screaming from the rooftops about this? With enough funding... like, wow, we could save tens of millions of people within a decade or so, I'd venture to say. (But the difference between the two techniques is that I think the funding push should be towards structure correctors, since that's a more realistic treatment option in the short- to medium-term.)

Brian


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