1. TAME – CD19-targeted B-cell therapy for post-infectious autoimmune ME/CFS using the monoclonal antibody tafasitamab: open-label follow-up study to a randomized, placebo-controlled Phase II trial of the CD19 antibody inebilizumab
   Principal investigators: Prof. Dr. Carmen Scheibenbogen & Dr. Judith Bellmann-Strobl 

2. Genetic Determinants of Post-Infectious ME/CFS: a 50-Family Study
   Principal investigator: Prof. Dr. Nataliya Di Donato

3. STRAT4PAIS — Immune Endotypes of Paediatric Post-Acute Infection Syndromes (PAIS): Mechanistic Stratification of ME/CFS and Related Post-Infectious Conditions
   Principal investigators: Prof. Dr. Marc Nikolaus & Fabian Dannenberg & Prof. Dr. Tilmann Kallinich & Dr. Mir-Farzin Mashreghi

4. Molecular dissection of cell death-mediated inflammation as a driver of virus-induced ME/CFS
   Principal investigators: Dr. Gregor Ebert & Dr. Stefanie Bader 

5. Myoflame-19 Autoimmune Substudy: GPCR Autoantibodies as Mechanistic Biomarkers of Endothelial Dysfunction in Post-COVID ME/CFS
   Principal investigators: Prof. Dr. Valentina Puntmann & Prof. Dr. Eike Nagel

6. Analysis of T-cell and B-cell receptor repertoires via single-cell RNA sequencing in patients with ME/CFS and post-COVID syndrome
   Principal investigators: Dr. Katja Schmidt & Prof. Dr. Thomas Harrer

7. MARK-ME – Minimal Biomarker Panels for Diagnosis and Stratification of ME/CFS
   Principal investigator: Prof. Dr. Birgit Sawitzki

ME/CFS Science have done an analysis using genetic data on pathogenic variants from Decode ME combined with RNA data which tells you which genes are actually expressed. This type of analysis is used in lots of other diseases to show which kind of cells are part of the disease process

In ME/CFS results point overwhelmingly toward the central nervous system (represented here in orange)

It really seems more and more we’re gonna have to focus on the brain. 🧠 Which tough because it’s hard to study and hard to get treatments into there too. But then again, it might finally get us closer to understanding what to target in the first place.

https://skywriter.blue/@mecfsscience.org/3mr5cmkybzj2f

Dutch muscle research by @BraedenCharlton shows ME #pwME and #LongCovid both have fewer muscle repair cells. Satellite cells rebuild fibers. FAPs coordinate repair. When they are low, recovery from exertion fails.

Both patient groups start with reduced satellite cells and FAPs. difference is after exercise. In #pwME, FAPs drop further. In #LongCovid they stay at the same reduced level. ME shows an exertion‑sensitive collapse of repair.

https://www.amsterdamumc.org/download/ams-book-of-abstracts-2026

"The brain’s waste clearance system is impaired in people living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) which can lead to various symptoms including brain fog, Griffith University researchers have discovered

Brain’s waste-clearing ability impaired in ME/CFS patients

Credit: Griffith University

The brain’s waste clearance system is impaired in people living with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) which can lead to various symptoms including brain fog, Griffith University researchers have discovered.

The research demonstrates, for the first time, the impact ME/CFS has on glymphatic function which is responsible for clearing the brain of metabolic waste products and is mostly active during sleep and disengaged while a person is awake.

Lead author Dr Kiran Thapaliya from Griffith’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) said when the brain’s waste clearance system did not work properly, harmful waste could build up causing neuroinflammation.

“This study is the first to demonstrate impaired glymphatic function in ME/CFS using MRI, providing a mechanistic explanation for the inflammatory changes reported by other Australian and international teams,” he said.

“This suggests that dysfunction in the brain’s natural cleaning system may be a key driver of this condition.”

Professor Sonya Marshall-Gradisnik, NCNED Director, said not only did reduced glymphatic function cause brain fog, but also caused sleep disturbance.

“The study found worse sleep is associated with poor brain waste clearance, reinforcing the notion that sleep plays a critical role in maintaining brain health,” she said.

“We hope the results can pave the way for better diagnosis through the use of non-invasive procedures, and importantly, future treatment for patients.”

The paper ‘Disrupted glymphatic function and its relationship with sleep and cognitive impairment in ME/CFS assessed via DTI-ALPS’ has been published in Frontiers in Neuroscience."

link to article

Edit:

For anyone who is interested in more on this topic here is a video from jarred younger on the glymphatic system and me/cfs https://youtu.be/-3r0_24Qb5A?si=O0zH6b0fATmJN5uE

We had quite some discussion around this under the last post so I thought I’d share this here

An interesting study found by accident that people sick with FM, ME and MS often belong to a generic subtype that has a change in TSPO receptors.

Why is that important?

That’s a common tracer site used to measure neuroinflammation. Meaning the neuroinflammation in patients might be invisible to PET scans leading to false negatives. And there seems to be correlation with symptoms as well.

“Results

In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms.”

That MMT study wasn’t great but excited to hear they will trial mitochondrial transplants 🤞🏻

Chromosome: 1q25.1 Gene(s): RABGAP1L Proposed Role: Intracellular response to infection

Chromosome: 6p22.2 Gene(s): BTN2A2 Proposed Role: T-cell mediated immunity

Chromosome: 6q16.1 Gene(s): FBXL4 Proposed Role: Mitochondrial DNA maintenance

Chromosome: 12q24.23 Gene(s): SUDS3 Proposed Role: Regulation of microglial inflammation

Chromosome: 13q14.3 Gene(s): OLFM4 Proposed Role: Neutrophil-mediated immune responses

Chromosome: 15q21.3 Gene(s): CCPG1 Proposed Role: Endoplasmic reticulum stress response and autophagy

Chromosome: 17q22 Gene(s): CA10 Proposed Role: Synaptic transmission and chronic pain

Chromosome: 20q13.13 Gene(s): ARFGEF2, CSE1L Proposed Role: Inflammation and immune signaling

Simmaron Research, 76 people with ME/CFS.

After 90 days of low-dose rapamycin, fatigue and PEM improved as IMPDH2 activity fell, oxidative purines dropped, and mitochondrial reserve recovered.

No placebo group tempers the result.

Good to see them investigating the possible mechanism of action in low dose Rapa

The German Psyloco study testing psychosomatic group psychotherapy just finished and… produced null results. It didn’t help fatigue, anxiety or depression measures.

And that is in spite of using a waitlist as their placebo, so in short you don’t have an active placebo.

The paper conlcudes: "No statistically significant efficacy of the immediate group intervention over the waiting control condition was observed, across primary and secondary outcomes."

A new study identifies two promising biomarkers:

•GDF-15, a marker of mitochondrial stress
•and VCAM-1, a marker of vascular endothelial injury

As predictors for developing Long Covid. Patients whose symptoms persisted for at least 6 months maintained significantly higher levels of both markers, despite having little evidence of ongoing systemic inflammation.

So what we see is not based in high level inflammatory markers—but in signatures of cellular energy failure and vascular injury may lie the answer for predicting long term outcomes in Long Covid.

Full description: To protect our community, we prohibit recommending Cognitive Behavioral Therapy (CBT), brain retraining, or exercise, such as in the form of Graded Exercise Therapy (GET), as treatments for ME/CFS or Long COVID, as many patients find them harmful and their effectiveness remains unproven. Discussions about the science of these therapies are allowed, but direct recommendations or linking to websites or subreddits advocating these therapies, except for scientific discussion, are not permitted.

"Fluge and Mella's working hypothesis is that ME/CFS, in a subgroup of patients, may be a variant of autoimmune disease, involving antibodies in the plasma cells. ...For several years they have been researching treatment for ME with immunomodulatory drugs, which temporarily reduce the plasma cells in the blood, thereby also removing the antibodies." (Norwegian source)

In the pilot study, which had 10 participants, is submitted for for peer review. 5/10 seemed to have significant improvement, while 1 participant had short term benefits.

The 2nd phase study will be randomized, double-blind and placebo-controlled, with 66 participants conducting a 3 month baseline monitoring before treatment starts. This will establish each patient’s symptom variability, improving the accuracy of change measurement post-treatment.

Daratumumab works by binding itself to CD38 (a surface protein) expressed on plasma cells, T cells, NK cells, and myeloid cells. Once bound, daratumumab triggers immune-mediated killing of plasma cells via several mechanisms: recruiting immune cells (like NK cells) to destroy the target; activating the complement system, leading to cell lysis; stimulating phagocytes (like macrophages) to engulf and digest the plasma cell.

Rituximab, which depletes B cells, is today been seen as unsuccessful treatment, even though many study participants experienced symptom relief. The way it differs from Daratumumab is that it reduces formation of new plasma cells, while Daratumumab eliminates existing antibody-producing cells. Rituximab targets CD20(on B cells), while Daratumumab targets CD38(on plasma cells).

Daratumumab is considered to have less side effects than Rituximab, but there is still a risk of things like low IgG, anemia, espiratory symptoms, infections from other bacteria or virus due to lower immune function, low blood platelet count, low levels of neutrophils.

Mella and Fluge on autoantibody targeting in ME in Berlin conference spring 25 (YouTube)

(Norwegian)Øystein Fluge talks about the new study with Daratumumab for ME patients

TLDR; Theoretically, persistent autoantibodies are destroyed, which could lead to things like nervous system homeostasis. Daratumumab directly eliminate existing plasma cells already making harmful antibodies.There is however rebound risk of autoantibodies reappearing if daratumumab is not solving the root cause.

Today BioVie announced topline results of the bezisterim trial for long covid (NCT06847191).

Bezisterim is an experimental drug that is trialed for Parkinson and Alzheimer’s. It is an oral small molecule, blood-brain barrier (BBB) permeable, anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase. Bezisterim has been shown to selectively inhibit inflammation-driven ERK- and NF-κB-stimulated inflammatory mediators, including tumor necrosis factor alpha (TNF-α), without inhibiting their homeostatic functions.

Statistically significant benefits observed in bezisterim-treated Long COVID patients 
in pre-specified subgroups with high baseline fatigue, cognitive impairment, and/or post‑exertional malaise.

Bezisterim showed a consistent advantage over placebo on 21 out of 22 individual endpoints in the overall study population.

Michael Peluso said: „These results are among the most promising we have seen in this field so far and clearly warrant progressing to a confirmatory Phase III trial“.

They also have a conference call at 8:30ET today. They mentioned that videos will be uploaded, so hopefully we get more information there.

Some positive news: Felipe Correa da Silva, the leading researcher behind the post mortem brain autopsy and tissue analysis in ME/CFS, announced that he won a new Dutch grant called "Off Road." It is intended for curiosity-driven, high risk, high reward ideas and provides up to €100.000 in funding.

“For people living with ME/CFS, cognitive symptoms can be one of the most disabling features of the disease. With RememberME, I will explore whether hippocampal synaptic alterations are a potential mechanism for cognitive symptoms in ME/CFS.

Beyond investigating a potential biological explanation for these symptoms, I will also explore what human postmortem brain tissue can reveal about the cellular architecture underlying communication between brain regions. I hope this work can complement neuroimaging studies by providing a cellular perspective on the brain networks implicated in ME/CFS. We also plan to extend this framework to other brain regions very soon, in close collaboration with Prof. Sonya Marshall-Gradisnikl and her team - dr. Natalie Eaton-Fitch and dr. Etianne Martini Sasso.”

TLDR: Belgian study will look deeper into immune exhaustion in ME/CFS

I really think we need more and a deeper look into the immune exhaustion/deficiency aspect rather than just staring at inflammation. Excited about this one!

Now fully published! Scheibenbogen & Wirth

"Growing evidence indicates that, in addition to the noradrenergic system, several other neurotransmitter systems—particularly glutamate, serotonin and GABA—are dysregulated in ME/CFS. This imbalance, characterized by excessive excitatory relative to inhibitory signaling, may drive neural overactivation and autonomic dysfunction. These disturbances may cause key neurological symptoms and contribute to skeletal-muscle dysfunction that manifests as exercise intolerance, PEM, fasciculations, and cramps."

4,75 Million, at least 25% of the way there. Such important work, very glad to see this get off the ground.

Woah and already replicated, n=250 and n=150. this looks big to me!

“Conclusions SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy.”

Some potential good news for the commonly POTS comorbid folks among us:

Regeneron announces that Baloncibart reduced orthostatic heart rate and improved orthostatic symptoms in a Phase 2 trial for POTS.

“Baloncibart is a monoclonal antibody that blocks NPR1 and increases blood volume, thereby easing POTS symptoms.

The Phase 2 trial was 1:1:1 randomized, double blinded and included 82 patients, 150mg Baloncibart (n=27), 450mg Baloncibart (n=27) and placebo (n=28). Primary endpoint was the change in heart rate from lying down to standing (DeltaHR) at day 8.

Baloncibart 450mg reduced DeltaHR at day 8 with a least-squares (LS) mean difference of -11.4 bpm (p=0.0007) and at day 29 with LS mean difference of -7.4 bpm (p=0.0124). Baloncibart 150 mg reduced DeltaHR versus placebo at day 8 with LS mean difference of -9.5 bpm (p=0.0045).

Furthermore did Baloncibart 450mg improve orthostatic symptoms, physical tunctioning, and activities of daily living versus placebo at day 29, as measured by the LWPQ.”

“The first clinical trial in the series will test the monoclonal antibody Pemgarda, along with the immune-modulating drug hydroxychloroquine. The study will include arms with both drugs by themselves and the two in combination.”

Department of Defense grants always seem comparatively small but they have a good track record of being efficient with their money. It’s the same institution that funded the promising Bezisterim trial we’re waiting for results on. Very much a contrast to Recover imo.