Dr Ron Davis - Updates on ME/CFS research - September 2019 onwards

"Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria."

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome, 2023 Hwang et al

 

Thank you Andy, I had missed that one. A futher question, and you're probably the person to ask it - is it possible that DecodeME could hypothetically find an association with this protein, if it turns out to be a factor? And would DecodeME finding no association with WASF3 mean that it is not actually a factor?

Also a question for everyone else- does anyone know if recover is looking into WASF3 for long covid? You would bloody hope so but I can probably guess the answer.

 

If elevated levels of WASF3 had a genetic basis and it was present in sufficient numbers of participants in DecodeME, then yes, it is possible that DecodeME would find it.

Perhaps, but it would very much depend on the results. It might be that elevated WASF3 might be due to some other disrupted process that we potentially find evidence for.

 

Ron Davis was saying the complete opposite a few years ago.

28:24 The results of that is basically there aren't virus infections that are different from healthy controls. A few people do have them but healthy controls have more in this small study, so it makes me suspicious that in fact they don't have viral infections. They have something else going on that feels like a virus infection and a lot of inflammation things things will make you feel like that. Most of these viruses probably, by themselves, don't really do anything by themselves. It's not to their advantage to give a signal to the body that they're there. The body is the one that does the signaling that there's something wrong. And I think if you have that signal like inflammation it may feel like a viral infection. The only reason I'm stressing that point is that if it's most likely you don't have a viral infection you shouldn't be taking antivirals probably, because they're probably not that healthy for you. And the reason they're probably not that healthy is that the antivirals generally target the synthesis of the DNA from the virus and it works because it's a very primitive

 

It's all just in the original paper. They built a transgenic mouse with extra copies of wasf3 and found it was crap at running. tbh my memory was that they used tudca and salubrinal on the mice but actually those drugs were used on patient cells in vitro (as seen in figure below). My guess is they will have tried these drugs on the transgenic mice and saved it for the next paper. fingers crossed!

 

This.

The Hwang paper does not suggest a genetic cause for elevated wasf3. It suggests it is downstream of endoplasmic reticulum (ER) stress. Perhaps there's a genetic reason for the ER stress but I wouldn't expect to find a direct wasf3 genetic issue.

Here's a few anonymous samples they tested for wasf3. It was higher in mecfs, on average. You'd love to see a provocation study where patients were measured before and after exercise (seeing how exercise is meant to provoke ER stress). Unfortunately wasf3 is a lightly-researched protein and testing for it is not a trivial matter so replication by any old lab won't happen.





A reminder of the central finding of this paper: something provokes ER stress -> ER makes wasf3 and pumps it into mitochondria -> wasf3 affects mitochondrial supercomplex formation -> making respiration inefficient. A side-finding is that the ER stress response looks weird, BiP and PERK should correlate but in mecfs they don't.

Just to tie this back to Ron Davis, before I get the thread totally off-target,
Hwan's wasf3 finding and Ron's itaconate theory start off on unequal footing. One comes from observation, a weird thing noticed inside one patient. The other, the itaconate shunt, is more of a theory. So I've got more hope in the wasf3 mouse model than the itaconate zebrafish model. Still, both might show us something!

 

Very interesting thanks. What's the latest we've heard from Hwang? Is it just a case of wait and see? I'm excited to see where this goes next!

I really hope RECOVER looks for WASF3 in long covid. It might be something to suggest at the meeting in September.

 

@V.R.T.

Re: meeting in September, Paul sent me this note a few weeks ago:

"I have now subscribed to the RECOVER network. I look forward to seeing the kick-off meeting agenda when available and attending some of the relevant presentations."

 

Thank you! That sounds promising. But I'm not entirely clear what 'subscribed to the RECOVER network' means. Does it mean he is eligible to apply for funding to run studies through the RECOVER program? Or an active part of RECOVER? Or just that he's on the mailing list, so to speak.

P.s. mods - sorry for pulling the thread off topic, feel free to move these posts and apologies if I've made anyone more work

 

It meant subscribed to the RECOVER updates and newsletters via the signup on their email mailing list.

I forget if you've mentioned that you messaged with Paul too but feel free to initiate any correspondence if you have further questions that I may not be able to answer

 

Thank you.

I haven't messaged with Paul. I remember seeing that he had been inundated with responses about drug trials and the like, and was hoping to do a clinical trial or a study but couldn't say more at that point.

But it would be interesting to know what has been going on since then.

I may drop him an email at some point but I am severe so I don't know when I'll get round to it. I've never really communicated with ME researchers before.

 

From the thread about the NIH conference in May.

 

https://twitter.com/user/status/1829306936753340737


Ron Davis today at the Santa Clara County ME hearing: “..we think this disease is initiated when you initiate innate immunity…you can turn it back off by JAK-STAT Inhibitor…we have seen 1 patient in Australia who took it..within 3 days of taking the drug was completely cured..”

 

This raises a few questions to me.

1) What is the stimulus?
2) Is the response to stimulus abnormal? (& how)
3) Which pwME does this apply to or in which combinations?

It seems these drugs are used to treat RA in Australia. I am guessing that a good number of pwME will be taking these for other diagnosed inflammatory conditions at the very least. My guess is that they haven't all been "cured" (no shade, I dislike the implications of the word in general). @Jonathan Edwards thoughts?

 

I agree, the comments quoted do not mean much.

Since CRP is not raised in ME/CFS, for a kinase inhibitor to help you would I think need to have macrophage activation without involvement of the usual pathways involving IL-6 and TNF. That may be possible but one person feeling better after a few days isn't much use to us in the context of ME/CFS research.

 

I have heard anecdotal accounts on the long covid sub reddit of precisely this. In the context of Wes Ely’s Baricitinib trial, people saying they take it for RA and it hasnt helped them. There may have been others who say it has helped them but I can't recall right now.

It may well help a subset which would be huge but I highly doubt its a miracle cure. I wish Ron Davis would stop making broad and poorly evidenced statements like these, it undermines his credibility and ours more generally. I don't doubt his good intentions for a second but I find it very frustrating.

Still I wish someone would fund him properly so he could at least trial this/abilify etc.

 

@Jonathan Edwards @DMissa, is there anything relevant in the work of this company which is developing more targeted anti-inflammatory and “immunometabolism” drugs? Luke O’Neill has said he thinks the underlying science will be relevant to long Covid and ME but it’s not an indication they are currently looking at.
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00899-4
https://pubmed.ncbi.nlm.nih.gov/35235776/
https://www.sitryx.com/pipeline

 

https://twitter.com/user/status/1829474605469409674


Janet Dafoe
This was at a hearing with three speakers who spoke for about a half an hour each and at the end the public got to talk. Ron had two minutes. He couldn’t explain the whole model and he couldn’t explain all the details!

 

but but but... Publish findings.
N=1, is it reproducible? can you confirm that # 1 is still fully recovered, back to normal, able to work out and live a full life for at least 6 month?