From Huntington treatment to AD treatement?

[J11]

Tom, I think one of the great features of this forum is that many here have taken the point of view that they are in charge of their health and they want to be fully educated about what their best options are. When you noted in your last post about
"If they can get ..." it made me think of how often people will say "We'll let them" solve our problems. {This is not how you intended it in your comment though it has me thinking about the "they'll take care of it" attitude versus the "I'll take care of it".)

Admittedly having to think through one's own perspective on various issues can be challenging. I realize that, though once you push through the uncertainty and certainly a considerable amount of inertia, you arrive at the invigorating point where you have the confidence to think for yourself and assert what you want for yourself and not like "them" tell you what to think.

I could clearly feel the frustration of many on the thread when we discussed the idea of whether genetically selecting against a future of APOE epsilon 4 would be something They would want. When I read the very very strong phase 2 results that were posted for the Methylene Blue trials (halted disease progression for at least 2 years-- no other currently approved AD medication has ever convincingly demonstrated any disease modification) I also thought about how people could assert their legal Right to Try the treatment that they wanted.

Moving this proactive status does take time, though once achieved it can be very liberating.

[Fiver]

Hi J11. Yes, I agree. This is a place where people should be proactive and pushing forward.

I'm in an odd position myself - arrived here looking to help my mom, sometimes take a (selfish) interest in prevention, and I also work in the field (in a small way). I've found the only way it works is to carefully keep some emotional distance, well, as much as I can.

About the Methylene Blue studies. I'm reading those. My first thought was that it is such a common lab dye. A long time ago - before regulations and modern common sense prevailed - it was a practical joke to put some in a friend's drink and have them wonder why they urinated blue the next day. (Obviously, that's not something anyone would endorse today. That was the era of no seat belts or helmets and nearly everyone smoked) So many twists and turns in all of this.

[J11]

Tom, if you like you could post additional comments about MB to the "Did MB really fail?" thread.
The big problem here is that oftentimes no one will do the required reading. Someone else is
expected to do the leg work, though no one bothers. It appears that much of the reporting and
commentary on MB was by those who did not the background reading. It would be great to discuss
this with someone who has taken the time and effort to plow through the convolution and confusions
in the MB research. From what I now understand MB/LMTX is a cure for Alzheimer's. It stopped
neurodegeneration for at least 2 years; currently approved medications do not stop neurodegeneration
for any length of time.

I have read through the phase 2 and phase 3 articles and the article explaining why the phase 2 had problems article
among others. These articles have convinced me that MB/LMTX is a very effective anti-dementing agent.
Before I took this effort I though taurx's explanations for the various problems they had in the phase 2 were mere hand-waving.
Sort of like throwing a dart and then after the fact creating an elaborate post facto (and blatantly obviously self-serving) explanation.
With taurx, it seems every time they throw a dart they have had to do this.

In the phase 2 trial, the gel caps did not work properly so the high dose became a low dose.
The MB then wound up in different parts of the GI tract which affected absorption and of course
there was an interaction with food. While the gel cap issue was appreciated before the fact, it still
makes it extremely confusing to unravel. AD treatment research should be less not more confusing than
the underlying disease itself.

[Fiver]

"AD treatment research should be less not more confusing than the underlying disease itself."

J11 - that'd be great, for sure!

...but in my limited experience research is a messy, painfully slow business of fumbling around in the darkness. I suspect we will stumble onto some helpful treatments - maybe like this RNA silencing approach - long before we understand the disease fully.

I'll try to read those articles soon.

[Harrison]

I don't think the anti-sense oligonucleotide is selective for apoE4 (and that level of specificity might be hard to achieve). I think they are going with the idea that ApoE4 + Abeta = not good, and if you lower apoE (not necessarily getting rid of all of it), you will decrease plaque formation. The practical limitation of this work is that you would need to treat someone in their 40s or 50s at the latest before there is a lot of plaque. Unfortunately this kind of prevention trial is an incredibly long, expensive venture that a pharmaceutical company would not take on lightly. If it can be shown that lowering apoE has other benefits and you could treat someone in their 50s or 60s, that would be a more manageable clinical trial.

I have merely glanced at the TauRx work and do not wish to pass judgement at this time. I am struck however, by the amount of resistance from the AD field about the possibility of methylene blue/LMTX actually working. I am not sure if it is healthy skepticism of arrogance, but few AD researchers of note seem to believe it. As long as TauRx keeps on persevering and are finally able to run a definitive clinical trial, we will eventually know.

[Julie G]

Does anybody remember the strange history of methylene blue as it relates to Alzheimer's? I can't find specifics, but I think it was initially trialed as a control against some promising Pharma years ago. It was considered a big joke at the time; the control outperforming the actual drug. In this latest phase 3, the low dose was the control and it ended up outperforming again. If a fish tank cleaner "control" ends up being a significant player in treating AD, we'll know God has a sense of humor .

BTW, (connecting dots today) it also treats nitrate poisoning and high levels of ammonia discussed here.

[J11]

Tom, I was going for " Dementia research should not be more demented than those with dementia." though often the words just
are not there for me. There are some highly accomplished writers on forums o one must always be careful. The problem is
that I do not think anyone believe my excuse that English is my Second Language (It isn't). I mean how could someone be
so close to native ability and though just fall a step or two short? It does not seem likely to me.

This is exactly correct about the messy nature of scientific research. This is the big reason that I have stayed away from the MOA question for MB. After all these decades of research it is still not clear that they have fully resolved the MOA of SSRIs one of the most
frequently prescribed drug class. I think stage 1 should always be to provide undeniable evidence of effectiveness and only provide descriptive reports (not speculations on MOA) during the initial round of research.

Thank you very much for offering to read the articles!
I fully understand that doing the required reading can often be an inconvenience.
I vividly recall my refusal to complete a required reading on a seminar investigating the
Post-neo-colonialist perspective of Feminist Neo-Marxists. I did not want to tempt fate
and experience neurodegeneration during my teenage years. However, I do not feel that
this shortcoming should condemn me to an eternity of like refusals to do required readings
for those on thread.

The MB/LMTX literature is confusing. It will be only when some carefully read the articles
that any meaningfully informed dialogue can ensue. From what I understand now, very few
have done this background work.

[J11]

harrison, thank you for the clarification on the ASOs. I was quite surprised when reading the report on them on alzforum that
even with the CAG repeats in the huntingtin protein they still were only able to knock down the overall protein expression and not the
specifically pathogenic form. As a guess, one might think that this might be possible?

I am also disappointed about the stance that the FDA probably has on this. APOE epsilon 4 is THE major genetic factor in Alzheimer's.
I am quite sure that many on this forum would be quite happy if there were some magical way to change genotypes to 33. It is frustrating that the protein itself cannot be understood as the biomarker in need of change without any reference to cognitive benefit. Creating a more grandiose requirement of showing actual cognitive benefit means that one of the most promising and rationale treatments might be decades from the market.

This is very true about the very negative commentary by the AD research community about MB. I accepted this interpretation until I carefully read the surrounding articles. Taurx's entire clinical strategy makes it very difficult to evaluate their pipeline. The issues that arose in their phase 2 and phase 3 trials would typically be resolved during a phase 1 trial. Yet, they raced LMTX into phase 3 without doing the foundational research first and then yet more issues arose. I am not sure that I even remember from ICAD 2016 that they have now shifted to claiming that the placebo dose of LMTX is more active than the treatment! The whole thing is such a major migraine. That is why it is so important that everyone are fully versed in what the articles themselves actually say.

[J11]

Julie G, the phase 2 trial did have some twists and turns.

However, it was a large randomized trial that had proper placebo control.
It found that there was a very large benefit to taking MB at a dose of 138 mg/day for up to 2 years.
The first graph in the MB AD Cure Celebration Thread shows near stabilization of cognition in those
on MB. Those on the blinded placebo experienced typical AD progression.

The problems with the dosing that arose in the higher dosing arm was then subsequently studied
and a highly plausible explanation for the discrepancy given.

It is not clear to me what valid criticism still remains for this trial.
The trial appears to have reported a fairly clean and very large anti-dementing effect for MB in Mild/Moderate AD.

http://taurx.com/phase-2.html

[Harrison]

I can't find specifics, but I think it was initially trialed as a control against some promising Pharma years ago. It was considered a big joke at the time; the control outperforming the actual drug.

Hi Julie, I believe you are thinking of a different clinical trial where the placebo outperformed the drug, so they went into phase II with the placebo. It was either an antibody or an oligonucleotide. I can't seem to find the reference to it right now. As J11 has described, methylene blue has had its own twists and turns.