Klimas/NOVA gene expression, treatment avenues

Belbyr

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https://www.sciencedirect.com/science/article/abs/pii/S0149291819300475

Abstract
Purpose
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration–approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
Methods
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
Findings
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
Implications
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation–based treatment strategies. (Clin Ther. 2019;41:XXX–XXX) © 2019 Elsevier Inc.
 

Wishful

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That fits how I think of ME. A bunch of genetic factors are shifted slightly, in ways that allow the immune system to feed back on itself and lock into an abnormal state. I doubt that they'll find 'the gene' or even 'the complex of gene variations that all ME patients have'. There will likely be subgroups with different patterns that lead to the same thing.

I have hopes that the right immunomodulators will be able to switch me out of this feedback loop, but each one will probably have some sort of problems associated with it, so it might need individual experimentation to find the best 'cocktail', and that might need adjustment over time. There might also be similar genetic variations with metabolic functions, membrane creation, etc, so they should look for that sort of thing too.

Perhaps they could try different immunomodulators on some patients? Start with the least potentially harmful.
 

Belbyr

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I bet the members from her group talk about this, this week in Australia since it was just published. Wonder if there will be any updates on the ‘system reset’ trials too..?
 

Belbyr

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ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation–based treatment strategies

I wonder if that final sentence means all ME/CFS is autoimmune/autoinflammatory? I know there have been plenty of people helped by things like Rituximab, IVIG, and plasmapheresis, but what about the failed stage 3 of rituximab or Whitney Dafoe not getting better on IVIG... I'm sure there are others.
 

Wishful

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The sentence doesn't involve autoimmunity or autoinflammatory at all. Dysregulation could mean an abnormal response to normal levels of immune system stimulation. Just failing to return to normal after activation would fit that description. There's no reason why ME has to be an immune response to our own proteins or other biochemicals.
 

used_to_race

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ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation–based treatment strategies

I wonder if that final sentence means all ME/CFS is autoimmune/autoinflammatory? I know there have been plenty of people helped by things like Rituximab, IVIG, and plasmapheresis, but what about the failed stage 3 of rituximab or Whitney Dafoe not getting better on IVIG... I'm sure there are others.
I don't want to spread misinformation, but I thought Whitney was doing a very low dose of IVIG. Also I believe his fatigue was worsened but I don't know if that means his other symptoms also worsened. Maybe some improved but they still decided to stop. It's hard to conclude anything about the general patient group from one person's experience with a low dose of a medication.
 
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Has mycophenolate mofetil been considered in the context of increased T cell clonal expansion (Stanford finding)? It will be interesting to see how Cyclophosphamide pans out with regard to reducing cytotoxic T cells.
 

Belbyr

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Has mycophenolate mofetil been considered in the context of increased T cell clonal expansion (Stanford finding)? It will be interesting to see how Cyclophosphamide pans out with regard to reducing cytotoxic T cells.
I could be wrong but I believe they just reported there is no T cell expansion when compared to controls, I thought I remembered seeing a slide of this at the Australia summit.
 

nandixon

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I'm cross-posting this info since this is actually the thread where it belongs:

It's never been clear whether the elevated TGF-beta commonly seen (and statistically shown by meta-analysis) in ME/CFS was a good actor helping to offset an inflammatory process, or if it was in fact causing more harm than good.

But in the fulltext* of the recent Klimas & company publication of this thread:

https://forums.phoenixrising.me/threads/klimas-nova-gene-expression-treatment-avenues.75491/

Klimas is now considering the possibility that it may need to be addressed and states:

While TGF-b was associated with protein kinase inhibitors, selective immunosuppressants, pyrimidine analogues, platinum compounds, anthracyclines, and antineoplastic agents, no specific FDA-approved drugs are known to target TGF-b, although this is an active area of development.66,67 As such, the TGF-b pathway was highlighted in both the male and female cohorts, was shown to be associated with several fatigue measures in the female cohort, and has been shown to be consistently elevated in ME/CFS.7 Thus, TGF-b inhibitors may prove to be a viable treatment avenue for this illness.
(My bolding)

*The fulltext is available here as a PDF download.
 

used_to_race

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I could be wrong but I believe they just reported there is no T cell expansion when compared to controls, I thought I remembered seeing a slide of this at the Australia summit.
It would be cool if we could get this confirmed one way or another. Last I heard, they were finding a subgroup where T cell expansion is definitely occurring, and a second subgroup in which the situation is unclear. Given the number of T cell suppressing therapies available for autoimmune diseases, this seems to be a promising treatment avenue that could benefit a variety of patients. Some severe cases could see benefit from drugs like azathioprine and methotrexate that outweigh the risks of those drugs, but there are also better-tolerated medications like abatacept which are apparently being used by many rheumatologists and regarded as pretty safe (despite possible cancer concerns down the road). A lot of these drugs have risks and side effects, but they are on the market and available now. Many people could (maybe, obviously awaiting confirmation in published studies) get an immediate and meaningful quality of life increase from these.
 

Wishful

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I'm pretty sure that I tried methotrexate. No effect on my ME.

Suppressing the whole (t-cell) immune system doesn't seem like a good treatment plan (unless its the only option). I'm hoping for something more precisely targeted, such as affecting a single cytokine and boosting some particular mitochondrial function. I quite like the concept of an immune system dependent on chaotic variation, which has become locked into an abnormal state. Hopefully, 'kicking it' in the right direction will knock it back into normal operation. Suppressing the whole system seems less likely to accomplish that.
 

used_to_race

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I'm pretty sure that I tried methotrexate. No effect on my ME.
Maybe you're one of the people without T cell expansion - or whatever parameter marks therapeutic response to MTX. Maybe MTX isn't a viable treatment for any ME/CFS subgroup. We can't really know until we identify subgroups and markers for those groups. However, it's cheap and should be accessible to more people. Some folks diagnosed with an Undifferentiated Connective Tissue Disorder (not clear to me how this is distinct from ME/CFS, I have both diagnoses) have responded favorably to MTX. Others have mixed or negative results with the drug. The thing is that even with a disease like RA, patients may try and fail some therapies that are helpful for others with the same diagnosis before finding a drug that works for them. It's never a one-size-fits-all treatment. The difference is that access to these therapies is basically nonexistent for us, while there's a (relative) pharmacopoeia of drugs available to RA patients, mostly covered by insurance.

Suppressing the whole (t-cell) immune system doesn't seem like a good treatment plan (unless its the only option). I'm hoping for something more precisely targeted, such as affecting a single cytokine and boosting some particular mitochondrial function. I quite like the concept of an immune system dependent on chaotic variation, which has become locked into an abnormal state. Hopefully, 'kicking it' in the right direction will knock it back into normal operation. Suppressing the whole system seems less likely to accomplish that.
I agree, it's not a great option, but the suppression doesn't have to be absolute. It's a lot better than feeling awful every single day. You're describing a model of the disease that doesn't exist yet, it's barely more than science fiction at this point. Whereas if T cell activation is proven, these drugs are available and do work.