IDO Metabolic Trap Hypothesis Published Today

bctjr1993

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@HTester you mentioned gene editing as one possible way out of the metabolic trap. The way you talked about got me thinking it wouldn't be extremely complicated for you to do it. I mentioned your comments on gene editing to my doc, and he said that is not something that patients can receive yet in medicine. Is that true? How hard would it be for you to go the gene editing route? Do you know if it is even possible to do that?
Thanks!
 
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@bctjr1993 Your doctor is basically right, as far as I know, gene therapy/editing (CRISPR-Cas9) is only approved by the FDA to treat 2 diseases. One is a genetic eye disease, and the other one is a cancer. For both of these diseases gene editing was god awful expensive to bring to the market and fetches a price tag from the upper middle 6 figures to over 1 million. Even with the huge price tag, there’s no guarantee it will work. I can’t find where you said Dr. Phair mentioned gene editing as a possible treatment, but IMO if that’s going to be the treatment for the trap it will be a minimum of 20 years before we might see a treatment.
 

FMMM1

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@bctjr1993 Your doctor is basically right, as far as I know, gene therapy/editing (CRISPR-Cas9) is only approved by the FDA to treat 2 diseases. One is a genetic eye disease, and the other one is a cancer. For both of these diseases gene editing was god awful expensive to bring to the market and fetches a price tag from the upper middle 6 figures to over 1 million. Even with the huge price tag, there’s no guarantee it will work. I can’t find where you said Dr. Phair mentioned gene editing as a possible treatment, but IMO if that’s going to be the treatment for the trap it will be a minimum of 20 years before we might see a treatment.
@bctjr1993 I corresponded with someone recently, who is much more knowledgeable regarding science i.e. than I am, and they felt that it's not clear that the metabolic trap is the correct hypothesis - from memory they pointed out that the incidence of the mutation(s) (in IDO2) is now considered to be 90% - of the whole population. Pity testing it is so difficult i.e. trying to measure very small amounts of tryptophan.

If gene editing is required then Ron Davis's comments come to mind - scientists overestimate what they can do in the short term and underestimate what they can do in the long term. According to one of the contributors on this program, 10 years ago no-one dreamed that CRISPR would be used for treatments [https://www.bbc.co.uk/sounds/play/b0bc6hkl ]. Yet today @Possibly James May highlights that there are two approved treatments.

One of my concerns is that we don't know what is causing ME; as Jonathan Edwards commented (Science 4 ME) we're still at first base. I'm hoping for some announcements i.e. of progress/insight e.g. Jarred Younger, in a video presentation - recent Conference in Sweden, suggested that recent experiments had worked out - they're currently preparing to publish the data.

Any news on the HLA/KIR work Ron Davis was doing?
 
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Regarding gene editing to treat human disease:
Bluebird biotech (NASDAQ: BLUE) has $6B in market cap. Their website is somewhat informative as to the diseases they have/are trying to treat using gene editing. https://www.bluebirdbio.com/

Also, Vertex treating ppl with 2 different types of blood disorders
https://www.genengnews.com/news/cri...from-trials-of-gene-editing-treatment-ctx001/

Gene editing will gain traction as the tools used to target areas of the genome become highly specific so as to reduce off-target effects.
 

FMMM1

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its not happening.
There are some reports on the key points from Ron's talk here https://www.s4me.info/threads/lives...-columbia-university.12407/page-2#post-219522

including this link https://paolomaccallini.com/2019/11/21/ronald-davis-at-columbia-university/

I have to say I found it interesting.

Nothing significant re trap i.e. no data saying we tested X cells and didn't find elevation of tryptophan (trap). An acknowledgement that the incidence of 1DO2 mutations is very high in the general population (%?) but all of the severely ill patients have it.

Selenium needed to convert to T4 to T3; selenium low in some of severely ill patients.
Is this thyroid problem currently commonly misdiagnosed?

Red blood cell deformability back i.e. seems to have been an issue with the medium. Potentially the problem re deformability is linked to something in the blood!

Think I noticed something about RNA viral work underway and bacteria (pathogens) as well.

At least they are working hard - let's face it Ron (like those reading this) has an interest in delivering!
 
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They are still working on the trap. Ron wouldn’t have spent 2 slides on it. There’s also info “on the street” that they are working on it.
These extremely difficult experiments take so much time, money, and expertise that we are not seeing, so it’s easy to lose faith, especially since most of us are in bed and don’t feel well.

edit: not 2 slides, but 4 slides on the metabolic trap
 
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Perhaps i was misinterpreting what Ron was talking about, it seemed like gene editing to me but I don't think he used those words
Yes, you can hear Ron mention what is very likely a reference to CRISPR-based gene cutting and pasting at 56:30 here: ("as we learn how to do genetic manipulation, and that's coming right around the corner")
 
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Yes, you can hear Ron mention what is very likely a reference to CRISPR-based gene cutting and pasting at 56:30 here: ("as we learn how to do genetic manipulation, and that's coming right around the corner")
I believe he was first referring to non-crispr technology before using the term genetic manipulation (which seems to be referring to crispr).
 

JES

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The IDO2 findings are the strongest suggestion that something could be going on with regards to the metabolic trap theory. Strictly speaking though, it's still more at a hypothesis stage than a theory. I have some doubts with regards to how the hypothesis fits with observed "temporary remissions", which is the thing I have been curious about the last few years. The perhaps most common temporary remission and one that Ron Davis spoke about as well is improvement during an acute infection, in my case, full recovery more or less.

The metabolic trap could perhaps be somehow temporarily circumvented during a cold through regulation and changes in IDO and kynurenine, which would make sense to me. But what I find harder to understand is this: since it is possible to reach a temporary remission, why does the sick "state" return back quickly after the cold, in a matter of a day or two? According to simulations, the metabolic trap requires a stressor and quite a bit of time as well for the tryptophan levels to rise enough for the trap to be sprung. If a cold takes you out of the trap, shouldn't it be possible or even likely to achieve a permanent recovery or at least not get back with ME/CFS symptoms right away.
 
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Violeta

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We're only speculating here, but one of my favorite ideas is that the stressors we all talk about as initiating the first crash do so by inhibiting IDO1 for long enough to build up the substrate Trp beyond the critical point. For example, nitric oxide is a potent inhibitor of IDO1. This could be combined with excess Trp in the diet, which some of you know is my hypothesis for how so many athletes and body builders have contracted ME/CFS.

In the Australian Dubbo study of infections, I think it was 9% had ME/CFS symptoms 6 months post-infection. These tended to be those who had the most severe infections, so we're thinking that's the immediate cause of increasing cellular Trp.

Then, of course, after cellular Trp increases beyond the critical point (defined in the paper), you can be cured of the precipitating infection, but you are still in the IDO metabolic trap.

If IDO1 is inhibited, for whatever reason, the consequences would be that it creates more causes of inhibition?

"Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called “kynurenines” that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity..."
 

Violeta

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I don't know if anyone will find this study helpful, but I will add it for possible application of remedies.

https://www.ncbi.nlm.nih.gov/pubmed/17430113

"Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases. "
 

Violeta

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IDO inhibition causes niacin deficiency?

Does niacin deficiency affect IDO2?

I see IDO hyper-activation can cause NAD deficiency.
" While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD."
 
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Violeta

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There is a drug called Beta-lapachone that is used to kill cancer cells by inhibiting IDO1.
Lapachone sounded similar to the active in gredient in pau d'arco, so I looked it up.

"Pau d'arco contains chemical compounds called naphthoquinones, specifically lapachol and beta-lapachone. They seem to have antifungal, antiviral, and antibacterial properties. They also contain significant amounts of the antioxidant quercetin."

I wonder how pau d'arco would affect someone if they used it for any length of time. (I drank it consistently for quite some time many years ago.)
 
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@Violeta, A while back Dr. Phair mentioned on the S4ME Forums his thoughts on IDO1 inhibiting cancer drugs.

The field of IDO1 inhibitors and cancer has been hot for years now, but as this Frontiers article highlights, most Pharma firms abandoned these programs with the first Phase 3 failure.

I was actually glad these drugs did not meet their clinical endpoint goals because I worried that they might cure cancer, but CAUSE ME/CFS if the IDO trap hypothesis is correct.

One of the valuable side products of this enormous effort by Pharma is that it produced vastly more research on IDO1 that we can draw on in the context of the trap. I'll talk about some of these benefits in the last few slides of my upcoming talk at the Stanford Symposium.