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Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread

dreampop

Senior Member
Messages
296
Regarding the recent Nanoneedle results from the drug Copaxone.

This was posted to the Facebook group "MECFS for the Slightly Irreverent" by Rachel Riggs, who is a patient, and the study coordinator / community liaison for Dr Robert Naviaux's lab.

"** Something really important happened this week at the Symposium, and I'd like to share it with all of you!! ‍♀️....

This is massive news, probably forum is quiet on a saturday.
 

nandixon

Senior Member
Messages
1,092
@Rachel Riggs
Thank you for the good work bringing Copaxone (glatiramer acetate) to Ron Davis's attention.

Did you happen to learn by any chance how quickly that the drug worked in the nanoneedle assay (hours, days, etc)?

And can you verify again that it took approximately 3 weeks after starting Copaxone for you to notice an improvement? Thanks again!
 

nandixon

Senior Member
Messages
1,092
I've been thinking a bit about your idea here. Assuming we can upregulate the genes that express IDO1, would launching more copies of the enzyme into an environment where they will be substrate inhibited help enough?

View attachment 29546

Looking at the above graph, yes, IDO1 can still make some kynurenine even at high levels of trp. But would it be enough?

Just eyeballing the chart, the flux produced by IDO2 can be 6 times higher than that from IDO1. Is interferon gamma enough to cause a six fold increase in expression of IDO1?
I'm making a second reply to your post because I noticed a few days ago a potential discrepancy in the data being presented in Prof Phair’s graph you attached compared to what is known in the literature with respect to the activity of the IDO2 enzyme.

In the graph(s), which is a Michaelis-Menten presentation with the y-axis labeled as flux instead of rate of reaction (because more than one enzyme is being evaluated), the plot for IDO2 would appear to give a Km value of about 200 micromolar (μM). (Km is the concentration of substrate, in this case tryptophan, with which the enzyme can achieve one-half its maximum reaction rate. The smaller the Km value the greater the affinity the enzyme has for its substrate.)

A Km of 200 μM for IDO2 seems to be much too small (i.e., too good) compared to the three literature values I found:

In a 2011 study, purported to be the first kinetic study of IDO2, a minimum Km was determined of “at least” 4060 μM. (The researchers weren't able to determine an exact value because IDO2 has such a low affinity for tryptophan and because they didn't use a high enough tryptophan concentration in their experiments,)

In a 2014 study a Km value of 6809 μM was found.

And in a 2016 study, a Km value of 9360 μM for IDO2 was found, which is experimentally very comparable to the 2014 value.

So the appearance is that the Km value from Phair's plot is on the order of at least 30 times smaller than one might expect. Although perhaps I've misinterpreted something or there's otherwise some simple explanation for the seeming discrepancy.

But if the above is correct, then IDO2 wouldn't seem to be very relevant in helping to bring down the elevated intracellular tryptophan levels Phair appears to have found in some ME/CFS patients. And indeed the literature is suggesting that there is probably no difference in tryptophan and kynurenine levels in people whether they have a functional IDO2 gene or not.

In fact, the growing consensus, since IDO2 was first discovered in 2007, seems to be that IDO2 is probably not very physiologically important as an enzyme with respect to the catabolism of tryptophan, and that instead its more important role may actually be non-enzymatic as an immunomodulatory or regulatory gene or protein.

So even though very common in the general population, it might be that a defective IDO2 in ME/CFS patients is somehow a contributor of the elevated tryptophan levels in the first place rather than not providing a way to decrease tryptophan levels that have caused IDO1 to become inhibited.

(Note that it should be relatively easy to at least test whether tryptophan catabolism is really needing to be increased in ME/CFS by using interferon-gamma in Ron Davis's nanoneedle assay in order to upregulate IDO1.)

In any event I very much like and appreciate the line of research that Dr Phair is doing and that the whole Ron Davis/OMF team is doing for that matter.
 
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Hopeful1976

Senior Member
Messages
345
Can anyone tell me how the metabolic trap theory links with gut symptoms?
Again, my gut is bad and wahey - all m.e symptoms have worsened. It is always the case. Intense Nausea/bloating/strange taste in mouth ect = more fatigue/depression/more pain ect. Why? According to Phair, what is the gut link?
 

Moof

Senior Member
Messages
778
Location
UK
I'm making a second reply to your post because I noticed a few days ago a potential discrepancy in the data being presented in Prof Phair’s graph you attached compared to what is known in the literature with respect to the activity of the IDO2 enzyme.

In the graph(s), which is a Michaelis-Menten presentation with the y-axis labeled as flux instead of rate of reaction (because more than one enzyme is being evaluated), the plot for IDO2 would appear to give a Km value of about 200 micromolar (μM). (Km is the concentration of substrate, in this case tryptophan, with which the enzyme can achieve one-half its maximum reaction rate. The smaller the Km value the greater the affinity the enzyme has for its substrate.)

A Km of 200 μM for IDO2 seems to be much too small (i.e., too good) compared to the three literature values I found:

In a 2011 study, purported to be the first kinetic study of IDO2, a minimum Km was determined of “at least” 4060 μM. (The researchers weren't able to determine an exact value because IDO2 has such a low affinity for tryptophan and because they didn't use a high enough tryptophan concentration in their experiments,)

In a 2014 study a Km value of 6809 μM was found.

And in a 2016 study, a Km value of 9360 μM for IDO2 was found, which is experimentally very comparable to the 2014 value.

So the appearance is that the Km value from Phair's plot is on the order of at least 30 times smaller than one might expect. Although perhaps I've misinterpreted something or there's otherwise some simple explanation for the seeming discrepancy.

But if the above is correct, then IDO2 wouldn't seem to be very relevant in helping to bring down the elevated intracellular tryptophan levels Phair appears to have found in some ME/CFS patients. And indeed the literature is indicating that there is apparently no difference in tryptophan and kynurenine levels in people whether they have a functional IDO2 gene or not.

In fact, the growing consensus, since IDO2 was first discovered in 2007, seems to be that IDO2 is probably not very physiologically important as an enzyme with respect to the catabolism of tryptophan, and that instead its role may actually be non-enzymatic as an immunomodulatory or regulatory gene or protein.

So even though very common in the general population, it might be that a defective IDO2 in ME/CFS patients is somehow a contributor of the elevated tryptophan levels in the first place rather than not providing a way to decrease tryptophan levels that have caused IDO1 to become inhibited.

(Note that it should be relatively easy to at least test whether tryptophan catabolism is really needing to be increased in ME/CFS by using interferon-gamma in Ron Davis's nanoneedle assay in order to upregulate IDO1.)

In any event I very much like and appreciate the line of research that Dr Phair is doing and that the whole Ron Davis/OMF team is doing for that matter.

Good spot! I can't pretend I fully understand all this, but I do follow your logic.

As Dr Phair said himself, the whole theory could be a red herring. He started by positing that any genetic mutation underlying epidemic ME must be common, otherwise the 'strike rate' would be very much lower; but we don't yet know whether epidemic and endemic ME are even the same disease, let alone whether genetics has much influence. He pointed out that any of the other theories of the underlying pathology could be correct.

That's what makes me feel so positive about all the work that's going on. Researchers are developing sound theories, they now have the technology to test them, and they're not wasting energy trying to protect their own reputations by knocking down others' work.

That's just one of the enormous gifts Ron Davis has brought: encouraging researchers to be rigorous but also generous. You have to be a bit of a maverick to take an interest in ME in the first place, so collaborating instead of competing might not be such a strange concept! As well as a famous object lesson in how not to do medical research, I think the ME field will eventually also offer future scientists a fantastic model of best practice.
 

raghav

Senior Member
Messages
809
Location
India
@Ben H Ben, can you give me the link to the video where Ron Davis talks about filtering the serum and checking the remaining contents ? I dont know where to look for it. Thanks in advance.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Re IDO Metabolic Trap

@Janet Dafoe (Rose49) @Ben H I think we heard loud and clear not to attempt to hack the kynurenine pathway ourselves. However, it would be really useful if Ron and Robert Phair could give us more clarity about things we might already be taking or doing? Are there things we should stop? Or should we carry on as normal?

From this thread and some googling, this goes beyond tryptophan and could involve nac, St John’s Wort, 5htp, SSRIs, coffee, melatonin, ketamine, B6, B3 and likely more. These are things which impact kynurenine or tryptophan levels and some of them pwme commonly take. Perhaps not taking them could cause other problems?

I might be over optimistic in this thought but although the IDO Trap seems too simplistic to be a full explanation of ME, it could turn out to be the only bit that matters. If you correct low kynurenine will correcting that reset ME, even if there are also other factors?! In which case finding the other factors wouldn’t really matter.
Probably there are Kreb cycle, ATP, immune, gut factors but these might be more influencing how ME expresses (symptoms and severity).

Eg in the Billing-Ross 2016 paper mitochondrial variants were associated with type of symptoms and severity but not whether or not someone has ME. So it makes sense that even if you edited the mitochondrial dna they might feel a bit better, but they’d still have ME. It is just pulling off a few leaves (if ME is like bind weed). If everyone with ME has IDO2 variants, although this may not say much about the individual experience or what it looks like above ground, it might be the root that needs to be dug up.

And indeed the literature is indicating that there is apparently no difference in tryptophan and kynurenine levels in people whether they have a functional IDO2 gene or not.

Is this in the links you gave?

But most of these people (at least with the common IDO2 variant) don’t have ME. If they haven’t experienced the 8 week stressor trigger wouldn’t we expect the tryptophan and kynurenine levels to be ok? The trap does require something else apart from IDO2 variants. I’m guessing they mean a stressor like EBV, rather than workplace ‘stress’ (almost everyone with IDO2 variants will have experienced workplace stress for 8 weeks ;)).

seems to be that IDO2 is probably not very physiologically important as an enzyme with respect to the catabolism of tryptophan, and that instead its role may actually be non-enzymatic as an immunomodulatory or regulatory gene or protein.

The gene IDO2 does seem to be important, but you think this isn’t much to do with tryptophan?

My variants:
A279169_D_DC60_40_D4_A220_8_ECF967_E69_E7.jpg

My variants (I have two though both heterozygous- are we expecting these to be dominant/ incomplete dominance rather than recessive?)

In Enlis I also looked up any variants I have in the Kynurenine metabolic pathway:
355_F0_F39_9_B87_4165_B23_C_DE8_E0_B516_D60.jpg


The combination of variants which are damaging and conserved in mammals looks promising. I think having deleterious score of 3 means these variants are in the top 0.13% on DANN in terms of potentially harmful variants. The variants I have also have high mammalian conservation scores (6.16 is highest possible? The R248W one is 6.0). I read that IDO2 is conserved as distantly as turtles and some fish. I don’t think IDO1 is conserved as much between species, indicating importance of IDO2.

But if @nandixon is right the importance might not be as described in the Metabolic Trap Hypothesis.

I’ve been trying to read up on the Kynurenine Pathway this week, and I’m making notes in a google doc (usually I understand and then forget!). Something I don’t understand yet is the difference between L-kynurenine (KYN) and Kynurenine Acid (KYNA). Can anyone explain? It seems like sometimes a substance can increase one and decrease the other?

The interesting variable here is that I am using a tricyclic antidepressant

I didn’t think it was a good idea to use SJW with antidepressants?
 
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Murph

:)
Messages
1,799
On Saturday, when I arrived to the Symposium, Dr. Naviaux pulled me aside immediately to tell me that when tested in the Nanoneedle Copaxone did indeed change ME/CFS blood to healthier blood. The only two drugs that have ever shown that result are Suramin, and Copaxone. I spoke to Ron Davis who also confirmed that. Later in the day, I ran into Rahim, the developer of the nanoneedle, who further confirmed that was the case."

That is AMAZING. Thanks so much for sharing that! I am off to look up Copaxone now.

EDIT: What did I learn:

  • It's a protein peptide made up of four small amino acids.
  • It got a really big good quality trial in which it was shown to reduce multiple sclerosis relapse frequency somewhat but not disease progression. It is approved for use in MS in many places.
  • It is referred to as an "immunomodulator". They talk a pretty good game but it is fairly clear they are still figuring out why or how this drug works in MS.
  • Side effects are common (mostly injection site reactions and flu symptoms) but can be severe.
  • It is now (or will be soon) available in generic form (the molecule itself is called Glatiramer Acetate, they've even run clinical trials to show the unbranded molecule works the same as the branded one.).
  • In Australian you can get the branded drug Copaxone which normally retails at $885.88 for $39.50 via the PBS.
  • There are very few papers on using Copaxone on conditions other than MS. I saw one on epilepsy. Quite a few on MS & depression. Not even much sign scientists are testing it in mouse models of other diseases.
@GodGenghis were there any more details from Rachel in the comments section of that post on the facebook group?
 
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raghav

Senior Member
Messages
809
Location
India
@jaybee00 Check this link out https://www.1mg.com/generics/glatiramer-acetate-212501?q=GLATIRAMER
Are you in India or where ? I dont think any Indian pharma is allowed to supply to US without FDA clearance. They wont do it. But Cipla is the cheapest at Rs. 375 / (Glatira) for a 20 mg injection. So that will work out to a little less than Rs. 12000 per month. But I am not sure whether you have to take it daily. Maybe like twice a week. Then it will be cheaper.
 

Moof

Senior Member
Messages
778
Location
UK
Yup, massive news about copaxone....

@raghav

Can you get legitimate quotes for a 30 day supply of Copaxone out of Delhi/Mumbai or wherever?

Thank you

It might turn out to be fantastic news, but I honestly don't think it'd be a good idea to try the drug outside of a properly-supported trial, especially given that Rachel suffered a serious allergic reaction to it.
 

jaybee00

Senior Member
Messages
592
@raghav

No not in India, but in India, a person could purchase this from a pharmacy, correct? Best would be to send a sample of all the generics, including the Indian generics to the Davis lab for testing.

@moof— my understanding is that copaxone is the most benign of the MS drugs—if you have an allergic reaction you can just stop.....
 

frozenborderline

Senior Member
Messages
4,405
Can anyone tell me how the metabolic trap theory links with gut symptoms?
Again, my gut is bad and wahey - all m.e symptoms have worsened. It is always the case. Intense Nausea/bloating/strange taste in mouth ect = more fatigue/depression/more pain ect. Why? According to Phair, what is the gut link?
. I don't think any researcher can simply explain all of the symptoms of ME/CFS. I'm happy that they are getting more specific. More specific focuses could eventually yield larger systemic results.
 

junkcrap50

Senior Member
Messages
1,330
Yup, massive news about copaxone....

@raghav

Can you get legitimate quotes for a 30 day supply of Copaxone out of Delhi/Mumbai or wherever?

Thank you

I doubt any Indian supply of Copaxone is possible. It is an injectable and needs to be kept refrigerated. Pharmacies in the US ship it on ice using next day air. You might be able to find an online pharmacies that offers it, but I would doubt it. It's likely not in as high of demand as most drugs online pharmacies offer. Plus, a little riskier injecting something bought online than a pill.

@jaybee00 Check this link out https://www.1mg.com/generics/glatiramer-acetate-212501?q=GLATIRAMER
Are you in India or where ? I dont think any Indian pharma is allowed to supply to US without FDA clearance. They wont do it. But Cipla is the cheapest at Rs. 375 / (Glatira) for a 20 mg injection. So that will work out to a little less than Rs. 12000 per month. But I am not sure whether you have to take it daily. Maybe like twice a week. Then it will be cheaper.

That website 1mg.com is a online pharmacy for Indians only. It is not one of these "online pharmacies" people buy from to get cheaper drugs in the US. 1mg does not ship outside of India. But there are lots of 3rd party, medication exporters that have websites. However, it should be said all of those medication exporters/online pharmacies are SKETCHY AS FRIG.

@raghav

No not in India, but in India, a person could purchase this from a pharmacy, correct? Best would be to send a sample of all the generics, including the Indian generics to the Davis lab for testing.

@moof— my understanding is that copaxone is the most benign of the MS drugs—if you have an allergic reaction you can just stop.....

Possible, but unlikely Davis would accept it. Research labs have their own sources for drugs and medication that are not pharmacies. They need to ensure that there is a high level of purification in the samples they test.
 

Rachel Riggs

Rachel Riggs
Messages
62
Location
San Diego
@Rachel Riggs
Thank you for the good work bringing Copaxone (glatiramer acetate) to Ron Davis's attention.

Did you happen to learn by any chance how quickly that the drug worked in the nanoneedle assay (hours, days, etc)?

And can you verify again that it took approximately 3 weeks after starting Copaxone for you to notice an improvement? Thanks again!


I took Copaxone twice. The first time for several years and it completely returned me to normal daily activity. The second time, in 2015, just months before my ME/CFS diagnosis, I noted about 3 weeks in that I was leaving the house and able to do things around the house with much more ease.
 

Rachel Riggs

Rachel Riggs
Messages
62
Location
San Diego
Did the woman who responded to copaxone get a further diagnosis
I wondered about genetic leukodystrophy
It can sometimes be misdiagnosed as MS
Or ADEM/TM and EAE does copaxone work well for those

The mystery protein might be naturally present just not folded or cleaved properly

My MS diagnosis was weak, I had very few lesions, all of which would resolve over time. Also, I noted that I was way sicker with much more diverse symptoms than those I knew with MS. The interesting thing to note is that there is no definitive diagnosis for MS, just as is the case with ME/CFS. It's a clinical diagnosis based on MRI's with space and time, and clearly mistakes are made. My point is that MS is not so different than ME/CFS in that way, yet the MS population is treated so much differently...
 

Rachel Riggs

Rachel Riggs
Messages
62
Location
San Diego
@Rachel Riggs
Thank you for the good work bringing Copaxone (glatiramer acetate) to Ron Davis's attention.

Did you happen to learn by any chance how quickly that the drug worked in the nanoneedle assay (hours, days, etc)?

And can you verify again that it took approximately 3 weeks after starting Copaxone for you to notice an improvement? Thanks again!
I'm so sorry, those details have not been shared with me, and I did not think to ask!