Review Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID, 2024,Warrayat et al.

Link: Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID - ScienceDirect

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID. This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients. Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Highlights

• Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are enigmatic diseases sharing many characteristics.
• The most debilitating aspects of these diseases are cognitive dysfunction, ‘brain fog’, and exercise intolerance, ‘post-exertional malaise’.
• There is no cure for these diseases; treatment is palliative only.
• Mitochondrial dysfunction with endoplasmic reticulum (ER) stress occurs in both diseases.
• Salubrinal inhibits the phosphatase that dephosphorylates phospho-eukaryotic initiation factor-2α (peIF2α), a protective protein for cells undergoing ER stress when phosphorylated.
• Salubrinal reduces the formation of Wiskott–Aldrich syndrome protein family member 3 (WASF3), a protein that causes mitochondrial dysfunction that is overexpressed in a cohort of ME/CFS patients.
• Salubrinal reduces WASF3 expression, restoring mitochondrial function in fibroblasts of a patient with ME/CFS.

 

If I'm reading the snippets correctly it seems that they did some in vitro experiments with fibroblasts of a ME/CFS patient with elevated WASF3 expression. Did they collaborate with the NIH WASF3 team to obtain samples from them, did a patient from said study connect with them, is this an entirely different patient or are all their statements conjecture?

 

Fortunately there is only one instance of 'CSF' instead of 'CFS'.

 

Salubrinal came to our attention via the Hwang study on WASF3. That study showed endoplasmic reticulum stress was causing WASF3 production and the WASF3 was screwing up energy production in the mitochondria by affecting supercomplex formation. (supercomplexes allow the mitochondrial membrane to work more efficiently). Salubrinal reduced endoplasmic reticulum stress and so reduced wasf3, and so permitted more energy production.

I agree. To my eye this looks like a piece of analysis you do ahead of applying for funding for a trial, or ahead of doing some in vitro work.



Nova SouthEastern University is where Klimas works, but she's not involved here, seemingly. Speth (last author) looks to be a very senior researcher there with expertise in the Renin-angiotensin system. https://www.robertspeth.com/



EDIT: I contacted the lead author and there's no funding, this was the initiative of
"some Pharm D students who had approached me about working in my lab. It was labor of love for us: translation – no funding ..., there is nothing on the drawing board for a clinical study as yet."

 

Haven't read it all yet but they seem to be arguing for a alternative: a compassionate-use exemption to perform a more limited study on cost grounds - Box 1 on p10:

 

It’s not a good drug candidate.

https://www.s4me.info/threads/wasf3...ome-2023-hwang-et-al.34776/page-5#post-489247