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

Solstice said:
https://twitter.com/user/status/1829436311020699831


Small thread about it with some comments from an MIT researcher. In response to what Davis was saying and what Ely David is doing with JAK STAT inhibitors.
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Interesting. I hope this other study gets funded. But it does really frustate me that Davis himself can't get trials funded. I don't believe he is our annointed saviour like a lot of pwME but he is incredibly intelligent and driven, and the NIH refusing to fund his lab for the last decade plus is outrageous.
 
Kitty said:
You'd think Open Medicine Foundation might fund some of the Phase I/II trials. Is there some reason why they don't?
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That is a very good question. Especially with abilify, Davis had a study of that ready to go and the NIH shot it down. I don't know where they're currently at with all the itaconate shunt stuff, perhaps they are not ready to do a study yet. JAK inhibitors obviously have serious side effects but you'd think at this point they might at least want to do a pilot study?

It also really frustrates me how they never publish anything.
 
Braganca said:
@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
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Without the impetus for a drug coming from a meanginful mechanistic study of pwME there isn't really much that anybody can say
 
On Reddit someone linked to a Robert Phair comment on Health Rising where he indicates the Australian patient Ron references was corresponding with him, Robert Phair. The patient had gone to Japan to seek Filgotinib, and got better within three days.

IN this webinar Phair also cites an anecdote about de Meirleir improving six patienst with Filgotinib. So at least it's not just one patient. But the quality of data is not high (yet).



Still, if science can come to understand why it works when it works, and why not when it doesn't, that could be very helpful. So in my view a trial would be worthwhile.
 
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Murph said:
Still, if science can come to understand why it works when it works, and why not when it doesn't, that could be very helpful. So in my view a trial would be worthwhile.
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Absolutely. Looking at the safety information in BNF, it's not something you'd take because somebody said it might work, possibly.

Important safety information For filgotinib

MHRA/CHM advice: Janus kinase (JAK) inhibitors: new measures to reduce risks of major cardiovascular events, malignancy, venous thromboembolism, serious infections and increased mortality (April 2023)

In 2022, the EMA conducted a review of all JAK inhibitors indicated for chronic inflammatory diseases and concluded that the risks associated with the use of tofacitinib could be considered a class effect (see Important safety information in tofacitinib). Following a further review by the MHRA, some existing warnings for tofacitinib have been updated and implemented for all JAK inhibitors included in the review, such as filgotinib.

Healthcare professionals are advised to:
  • avoid use in patients aged 65 years or older, in patients who are current or past long-time smokers, and in patients with other cardiovascular disease or malignancy risk factors, unless there are no suitable alternatives;
  • use with caution in patients with risk factors for venous thromboembolism;
  • use lower doses in patients with risk factors, where applicable;
  • periodically examine all patients' skin for malignancy;
  • inform patients and their carers of these risks, and the signs and symptoms that warrant urgent medical attention.
 
Murph said:
Still, if science can come to understand why it works when it works, and why not when it doesn't, that could be very helpful. So in my view a trial would be worthwhile.
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This was the rationale behind the LDA trial that was rejected (with the infamous 'its depression, give them antidepressants' aside to Ron). Why does it work for some people and what happens in the body when it stops working. Could possibly have taught us a lot.

Kitty said:
Absolutely. Looking at the safety information in BNF, it's not something you'd take because somebody said it might work, possibly.
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Yeah as a former smoker I would be absolutely bricking myself if I had to take this but the risk would 100% be better than severe ME if it had been shown to have an effect in a well designed trial. If they have a solid rationale for why it might work and a case study of someone responding (plus KDM's dubious info) a small trial might not be a bad idea. As long as people are fully informed of the risks.
 
The role of the electron transport chain(ETC).

Yes, the immune system can block ATP production in the electron transport chain (ETC) in a number of ways:

Glycolysis immune cells can switch from oxidative phosphorylation to glycolysis to produce ATP. Glycolysis is less efficient than oxidative phosphorylation, but it's important in times of hypoxia and can occur even in the presence of oxygen.

Itaconate can block complex II in the ETC, which prevents succinate oxidation and results in reverse electron transport. This can lead to increased ROS production, which stabilizes the transcription factor HIF-1α and enhances the inflammatory response.

Activated macrophages activated macrophages can manipulate the TCA cycle and ETC to modulate their immune function. For example, inflammatory macrophages have a “broken” TCA cycle, which blocks the production of ATP.

The ETC is responsible for generating ATP by coupling electron transfer with proton pumping. It also regulates the function of some innate and adaptive immune cells
 
I'm not sure if many people know this but myself and Rob Phair developed the itaconate trap hypothesis. We were looking for pathways to explain why amino acids may be preferentially used by ME/CFS patients and why this occurs rapidly as a stress response in all animal cells, especially more rapid and exaggerated in females.

We noted that CoA is needed for non-amino sources of substrate entering the TCA cycle, Rob actually first identified the Itaconate pathway as perhaps being involved and we discussed it's potential role and built out the pathways. This was particularly interesting because of the initiation by innate immune system. This is important because innate immune system seems to be relevant to ME, the broad array of triggers largely impact innate immune system and studies in trauma research highlighted that the longer the innate was elevated and adaptive was suppressed was the clearest predictor of a protracted recovery. It seems likely to us that something about the innate immune system and altered metabolism is important for ME, the Itaconate trap theory connects the two.

Of course it remains a theory that is to be tested, we have some efforts to test it in Melbourne, main efforts happening at Stanford and Utah, though Utah work is really looking at the impact of initiating this itaconate pathway on fatigue. We do think that we've stumbled on a factor underlying that initial hit of fatigue you feel when your innate system is ramped up against a stressor/pathogen. So I guess the suggestion is that either a chronic interferon response could be sustaining itaconate pathway in ME or there's an inappropriate ongoing elevation of itaconate pathway in ME or itocnate metabolism isn't much to do with ME chronically and may just play a role initially or no role to play at all.
 
MelbME said:
longer the innate was elevated and adaptive was suppressed was the clearest predictor of a protracted recovery
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Just in case it's relevant, I looked at the deep phenotyping study data and found that the neutrophil:lymphocyte ratio was pretty highly correlated to subjective brain fatigue. Less so to some neurocognitive tests, and I didn't test against anything else. But high innate, low adaptive.

forestglip said:
So first here's the data from the NIH study for NLR calculated from [Neutrophil Abs / Lymphocyte Abs] versus brain fog (calculated by summing relevant question scores in MFI and BFI questionnaires):
View attachment 24361
Spearman correlation = 0.707, p = 0.0022
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MelbME said:
This is important because innate immune system seems to be relevant to ME, the broad array of triggers largely impact innate immune system and studies in trauma research highlighted that the longer the innate was elevated and adaptive was suppressed was the clearest predictor of a protracted recovery. It seems likely to us that something about the innate immune system and altered metabolism is important for ME, the Itaconate trap theory connects the two.
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It might neatly explain why we're seeing so much ME/CFS with Covid. While maybe there's something special about SARS-CoV-2 and its various proteins, perhaps it's more a feature that this is a novel virus for the population. So generally everyone had to ramp up their innate response higher and for longer to get control, because a useful adaptive response wasn't yet available. If the odds of getting pushed into a pathological ME-state are a function of amplitude x time of innate activity, we'd expect to see more succumbing. Maybe then subsequent waves of Covid variants would show less people developing ME, which is more determined by similarity to a previously seen pathogen (no longer novel), rather than specific changes in the virus and its proteins. And of course we have quite a lot of data that vaccination is protective, which prepares the adaptive response and so would limit amplitude and time of innate activity on initial/subsequent infection.
 
It's an interesting idea. It's a bit hard to square with people getting ME/CFS on their second or third SARS-CoV-2 infections though - there have been reports of that. There's even been the suggestion that the risk of Long Covid following repeat infections isn't markedly different. But, the state of knowledge about repeat infections is still messy, it's hard to know what the real situation is.
 
Yes, that's a good point. Perhaps an explanation could be an inadequate adaptive response on the first infection, perhaps as a result of prior infection (immune imprinting), so that the second (or even third) exposure gives a similar risk to the first. And presumably with a genetic or other predisposition required as not every virus-naive infectee develops LC: maybe a two-or-more hit model.

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Previous Humoral Immunity to the Endemic Seasonal Alphacoronaviruses NL63 and 229E Is Associated with Worse Clinical Outcome in COVID-19 and Suggests Original Antigenic Sin (2021, Life)

Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases (2023, Science Translational Medicine)

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses (2023, Brain)

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection (2023, Nature)

Divergent adaptive immune responses define two types of long COVID (2023, Frontiers in Immunology)

Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2 (2024, Nature Immunology)

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Edit see also today's study of asymptomatic exposure associated with an early interferon response.
An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure (2024, Lancet: eBioMedicine)
 
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