OMF Kynurenine trial

[jaybee00]

https://www.omf.ngo/2020/04/26/kynurenine-clinical-trial-for-me-cfs/

Anybody know anything about this? Do you think Kyn. is administered orally or via IV?

 

[Wishful]

I'm happy to see any sort of research in this area, since I think that problems in the cerebral kynurenine pathway cause some (maybe most) of my symptoms. L-KYN crosses the BBB readily, but I'm not sure of bioavailability via oral doses. Sublingual should work. I think my problem lies downstream of L-KYN, so I don't think that supplementing that would help me.

 

[junkcrap50]

Yes, I would like to know the rational for choosing Kynurenine for use in a trial and what they're looking at. What's the hypothesized mechanism or outcome they're examining.

 

[Marylib]

@junkcrap50 It might pay to follow this blog. Paolo writes in both English and his native Italian, and he is good at explaining this: https://paolomaccallini.com/author/paolomaccallini/
He does need funds for his blog. Paolo has been ill for some decades.
This particular research idea involves Robert Phair's metabolic trap hypothesis.

 

[Rufous McKinney]

This is very exciting! This furthers the IDO Trap hypothesis....its looking at that pathway....Wish I could be a study victim.

Anyone familiar with obtaining chemicals? I"m just curious- so it seems like one can order: kynurinine....from a couple of sources. One, I pretended to order and it never showed up in the cart. Another site, I pretended to order and it lead me to -paying. Wants to know about the institution...so perhaps its thru some mechanism...one must show one is a researcher somehow.

I am wondering how these research chemicals are regulated. It is incredibly tempting to want to obtain some and....experiment! Oh, I wouldn't but still I'm very curious.

 

[ZeroGravitas]

Robert Phair's metabolic trap hypothesis.

Yup, see his personal thread with most of the Q&A discussion [here]. The trap hypothesis [paper] thread [here]. And a video explanation of his hypothesis [YouTube]:

Basically this is the relevant part of metabolism:



IDO1 enzyme only works well at low concentrations of it's substrate, tryptophan. So, if a person has a mutation in their IDO2 enzyme (as almost everybody does), then a very high tryptophan state in a cell can become chronically stuck on (trapped over the other side of the hump on the right chart):

Functional IDO2: Deleterious IDO2 SNPs:

If kynurinine is usually the main sink of tryptophan, throughput to serotonin may be boosted, causing autonomic neurological symptoms, if cells in the brain stem are affected. Kynurinine itself is also important for a host of downstream metabolites, eventually leading to energy production and other things. But also it can make cyto-toxic substances (I think?), so it could well be a double-edged sword (or just straight-up bad).

Krebs pathway diagram annotated with some of my own altered metabolite levels I'd had tested previously [sorry, please ignore raised/lowered markings]. Kynurinine shown lower middle:

It's exciting that OMF are pushing straight ahead with a clinical trial for this, even before concluding the lab cell modelling work [Phair's Update]. Science at pace. Although I wouldn't necessarily expect much from this trial, because of this. Maybe more of a 'just in-case' it turns up something...

 

[sb4]

@ZeroGravitas Why is Tryptophan going down in that image, should't it be building up as some downstream enzymes aren't working?

 

[ZeroGravitas]

Why is Tryptophan going down in that image

Agh, sorry to mislead, I'd just happened (at the time of making this reply) to scribble onto the diagram the altered levels of my own metabolites that I'd had tested, for reference... I should have made a new diagram really...

The alterations happened to seem to fit somewhat with the hypothesis, although there's no reason to think one would see that in the serum. Especially if it really is just a bunch of neurons in a vital part of the brain which are trapped, which is key.

 

[Wishful]

I don't get excited about research findings from serum. My ME seems to be in my brain, and the BBB makes serum testing unlikely to properly show cerebral levels. To make it even harder, there's a difference between spinal fluid and the fluid in the lymphatic vessels in the brain (I forget the proper term). I think that to really understand what's going on with ME, you'd have to take fluid samples from various points in a living brain, and repeat it before/after sleep and before/during PEM.

Any volunteers?

Some other options might still provide useful information. Tagged TRP or other kynurenines taken sublingually or intranasally. There are probably other chemicals to trace other pathways.

Then there's the shrink ray used on a submarine full of researchers...

 

[junkcrap50]

Yes, I would like to know the rational for choosing Kynurenine for use in a trial and what they're looking at. What's the hypothesized mechanism or outcome they're examining.

Sorry, I meant to say that I know it likely has to be a test of Phair's Metabolic Trap (kynurenine is what IDO makes from tryptophan), but how does it fit into the metabolic trap theory. Is it really as simple of providing more of the product in the pathway to try and shift the reaction leftward by balancing it? So, the concentration of tryptophan (relative to amount/concentration of kynurenine) is lower, thus moving IDO to the left of the hump/trap? I'd like more details how providing kynurenine would affect IDO1. Modeling the effect of adding kynurenine, I'd think, would be fairly simple. So hopefully, Phair has a good expectation of it helping.

 

[Wishful]

The kynurenine pathway seems pretty complex. For one thing, IDO is strongly affected by interferon (beta and gamma). I hope that Phair is at least thinking about IFN levels during the tests. My ME symptoms seemed more severe during events that would have elevated my IFN levels.

This paper on INF and IDO seems interesting...and way beyond what my brain is willing to wade through at this time.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040184/

 

[raghav]

When are the trials expected to start ? Which month ? Will they keep us informed during the trial or is it supposed to be kept under wraps ? The trial is for nearly 7 months. So if they keep us informed of the progress it will be nice ? If the trials succeed will OMF then have to look for FDA approval for a larger trial ? Who is the supplier ?

 

[Marylib]

I saw a several drugs involving the kynurenine pathway in this article. This is research for ALS. Personally, I think fooling around with these drugs as a patient might be a big mistake, but it's interesting if OMF is considering re-purposing these or other medications- would take time and money for trials, of course. Mestinon is a good example of a myasthenia gravis drug that's pretty easy to get that has caught on already.

https://www.researchgate.net/publication/221922811_The_Kynurenine_Pathway

 

[raghav]

Isn't kynurenine needed to make ATP in the end ? So by giving the cells required ATP might be the cells can then clear the overload of tryptophan ? Just a wild guess.

 

[Wishful]

KYN doesn't go directly into ATP, and those other products might be critical for the ME state. There's also the problem that not all mitochondria in the body are the same, so some might respond to supplemental ATP--or KYN--but others won't.

What I wonder about the trial is: is it being done because a significant number of PWME reported feeling better after taking KYN, or is it just a 'sounds theoretically good enough to get funding' trial?

 

[jaybee00]

Prob theoretical. I don’t know of anyone who tried kyn.

 

[junkcrap50]

What I wonder about the trial is: is it being done because a significant number of PWME reported feeling better after taking KYN, or is it just a 'sounds theoretically good enough to get funding' trial?

The latter. I don't think you can buy kynurenine as a supplement.

 

[Rufous McKinney]

I don't think you can buy kynurenine as a supplement

I somewhat tried to figure that out...it seems to exist for research purposes but I got to Google Search page 3 with no sign of- it being sold as a supplement....

Meanwhile: eat potatoes?

 

[Sam200]

I have been wondering whether limiting the intake of tryptophan may help our bodies bring the levels down themselves quite slowly. Then if tryptophan concentration lowers, the IDO1 enzyme would become more active again, increasing kynurenine and removing us from the metabolic trap.

From my investigating papers, it seems as though by ingesting high doses of various other amino acids that compete for absorption with tryptophan, it is possible to decrease the level of tryptophan being absorbed by our bodies.

This would explain why so many people have benefitted from taking high doses of BCAAs (like @Mary ) and proteins like collagen which do not contain tryptophan. This also seems as though it would be a lot safer to try than trying to find kynurenine and supplement with that.

Does my logic make sense to you or am I missing something? I have ordered some BCAAs to see if they improve my PEM when taken at each meal

 

[ljimbo423]

I have been wondering whether limiting the intake of tryptophan may help our bodies bring the levels down themselves quite slowly. Then if tryptophan concentration lowers, the IDO1 enzyme would become more active again, increasing kynurenine and removing us from the metabolic trap.

From my investigating papers, it seems as though by ingesting high doses of various other amino acids that compete for absorption with tryptophan, it is possible to decrease the level of tryptophan being absorbed by our bodies.

This would explain why so many people have benefitted from taking high doses of BCAAs (like @Mary ) and proteins like collagen which do not contain tryptophan. This also seems as though it would be a lot safer to try than trying to find kynurenine and supplement with that.

Does my logic make sense to you or am I missing something? I have ordered some BCAAs to see if they improve my PEM when taken at each meal

I take 13 gms a day of BCAA's and get a big energy boost from them and they also help to lessen my PEM. My understanding of how they are working is in the mitochondria.

This diagram is from the Fluge and Mella study that found the Pyruvate Dehydrogenase enzyme to be impaired in ME/CFS. Leading to the creation of lower levels of ATP.

In the pink box you see Ile* (Isoleucine, a BCAA) and Leu* (Leucine another BCAA). Both are feeding the krebs cycle by creating more Acetyl-CoA. These BCAA's were found to be low in ME/CFS. Val* (Valine) in the purple box, the third BCAA, feeds the krebs cycle directly. So by increasing BCAA's, the krebs cycle should create more substrates to create more ATP and energy.

Source

BCAA's might also have a role in helping if there is an IDO metabolic trap. I haven't looked into that though.