USA: NIH National Institutes of Health news

A recording and transcript will be posted on the NIH website soon.

A few points I picked up:
The 4 centres they funded a few years ago - Hanson at Cornell has renewed funding, the data center funding will soon be announced and for 2 more centers applications are still open, so presumably the other 2 current centers will be among the applicants.

The main talk was interesting hearing about the next stages of research they are doing and planning, but I think better to wait for the full version rather than trying to decipher my scrappy notes.

 

I did make the webinar. 204 attendees, it will be recorded.

Some notes:
Koroshetz had a conflict and couldn't make the call.

Vicky Whittemore: talking about the trans ME/CFS working group.
Making a Roadmap, to assess what we know and don't know.
Considerable efforts have been made to include people with lived experience in this
There will be webinars from June that the public can participate in.
They will be using a crowdsourcing tool to get input on research programmes
There will be a draft report produced at the end of 2023 which will be presented to the NINDS council in Feb 2024
There's an intention to fund an additional 2 collaborative research centres, as Trish said, in addition to Cornell, so presumably the existing centres will be applying, along with others
A young investigator conference is being planned.

Dr Nath: intramural study and beyond
The transcript of what he said is in a previous post
They are planning clinical trials based on the observations from the intramural study


Joe Green of NIH, part of the ME/CFS working group
Noted two areas of interest
Microbiome - production of butyrate differs in ME/CFS.
This was found by both the Columbia group (Lipkin) and Jackson Lab (Unamatz) - published papers
Highlights pathways where there could be interventions

Post-exercise effects
Cornell published two papers
March 2023, Moore lead author, After exercise testing the healthy controls took 2 days to recover whereas the ME/CFS people took two weeks. Quantitative measurement of PEM may be possible?
Small pilot looking at differences in urine metabolites. This will be followed up.

He encouraged people to visit the Data coordinating centre website, they are adding data all the time

NIH working Group is planning a meeting in December to talk about the status of ME/CFS research. It will be a public meeting with virtual access.

 

Dr Avik Roy and Dr Gunnar Gottschalk
NINDS has just issued a research award for their work on ATG13 [so perhaps that tells us something about what the intramural study found?]

they collaborate with Dan Peterson at Incline Village and are based at the University of Wisconsin. The lab there at the Milwaukee campus is focused on biomarkers, animal models and drug discovery. There was talk of making use of the drug discovery expertise.

They have two areas of focus:

1.mTOR activation causing autophagy impairment
There was a brief summary of their paper last year that found ATG13 consistently upregulated in people with ME/CFS. It was noted that the ATG13 was phosphorylated, and so, inactive.

There was a nice diagram showing that when MTOR is activated, it causes ATG13 to be phosphorylated, which inactivates it, stopping autophagy. When MTOR is not activated, ATG is not impaired and autophagy proceeds. Activated MTOR also affects other things, e.g. causing STAT3 to become phosphorylated, which affects IL6 and RANTES.

2. translation of this finding into a mouse model

There was a slide with a number of papers listed, with the suggestion that there are contributing factors. These are the papers:
Mitochondrial toxicity - Hansen et all 2016
Upregulations of inflammatory cytokines - Mandarin et al 2020
Myelin abnormality - Morris and Maes 2013
Autophagy impairment - Gottschalk et al 2022
[I wasn't sure what to make of that list.]

For the animal model, they have three strategies
a. drug-induced mouse model for PEM
b. transgenic mouse model, where ATG13 function can be knocked out of specific tissues e.g. muscles, brain, peripheral nervous system
c. virus induced or plasma infused mouse model

They have been working on a mouse model, using something called SIM501. [ I didn't pickup what that was.] After 5 days there were severe impacts on young female mice (it sounded as though older female mice weren't affected). There were some dramatic pictures of activity tracks. Before exercise the controls and SIM501 treated mice moved around their cage a lot. Then all the mice were exercised for 15 mins on a treadmill. All mice moved less the next day. But the SIM501 mice were still not moving the next day. After 14 days, the SIM501 mice had a loss of muscle mass and low growth. Their muscles showed waves consistent with a pattern called 'marching soldier', consistent with inflammatory demyelination. Increasing doses of SIM501 caused decreasing grip strength. There was massive infiltration of inflammatory macrophages into the muscles tissues, macrophages expressing CD40.

But the fatigue effect was transient. After a month, the mice no longer showed the PEM effect. Also the drug is not specific to ATG13, it affects other things too. [Like I said, I missed why they thought this drug might induce PEM. the slides showing differences were dramatic, but it may not have much to do with ME/CFS.]

Avik Roy thinks an MTOR modulator could improve the disease pathology. Rapamycin was mentioned. Some peptides could be designed to prevent disease progression in mice. There was a question about what might be causing the processes that affect ATG13 - Avik Roy said he didn't know.

There was a question about muscle biopsies, Roy said he was interested in those. Vicky Whittemore noted Cornell is currently recruiting patients for a muscle biopsy study. Roy said that he was very interested to see the tissue samples.

There was a question about the demyelination, what could be done to stop the process? [I don't think that we have proof of demyelination - it seemed to be just this mouse model created by injecting a specific drug into them.]. Avik Roy noted that there are drugs available for demyelinating diseases such as MS. He also commented that cinnamon has prevented myelin loss in mouse models - it sounded as though this was work that he had some involvement in.

 

Dr Nath was asked about the criteria used in the intramural study, the inference being that the MEICC criteria should have been used, and that there is too much focus on the one symptom of PEM. Nath replied that they applied several different criteria and that they were as sure as they could be that the participants had ME/CFS.

He also took a question about if muscle weakness is part of the illness. He commented that ME/CFS isn't muscle weakness, it is exercise intolerance, exhaustion after activity.


My overall impression was of activity and some enthusiasm from NIH for further work in ME/CFS. There also seemed to be a good emphasis on the participation of people with ME/CFS and carers in determining the path forward. Certainly the most positive NIH ME/CFS Working Group webinar that I have heard to date.

 

Some posts and a link to a video of the part of the call presented by Avik Roy and Gunnar Gottschalk have been moved to a discussion thread:
mTOR activation, ATG13 inactivation and suppression of autophagy

 

Some data out for the NIH ME/CFS study too - discussed here:
USA: National Institutes of Health (NIH) intramural ME/CFS study