ME/CFS: Why are there still no evidence-based therapies? Scientists struggle for research funding
Ute Eppinger
3 January 2025
ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) affects millions of people worldwide. The disease, often triggered by viral infections such as COVID-19, leads to extreme exhaustion and severe restrictions in everyday life.
Mitochondrial disorders are considered a possible cause. New therapeutic approaches such as MDC002 for mitochondrial regeneration are promising. However, researchers are having great difficulty funding studies.
20 million patients with ME/CFS worldwide
The figures for ME/CFS are rising: According to an interim assessment by the KVs Nordrhein (KVNO) and Westfalen-Lippe (KVWL), the number of patients who have been clearly diagnosed with ME/CFS has almost tripled in the two chamber districts within 10 years. The number of sufferers worldwide is estimated at 20 million.
The German Society for ME/CFS estimates that around 500,000 people are affected in Germany alone, 1 tenth of whom are children. Prevalence from the USA, based on a medical diagnosis, shows that 1.3% of adults were affected by ME/CFS in the period 2021-2022, with women being more likely than men (1.7% versus 0.9%).
Varied symptoms
ME/CFS causes severe fatigue in those affected, which is accompanied by many other physical and cognitive symptoms. Characteristically, the symptoms worsen after physical or mental exertion, which is known as post-exertional malaise (PEM).
The severity of ME/CFS varies, but the disease often severely restricts the lives of many sufferers: Almost 70% of German patients are unable to work, around a quarter are bedridden and dependent on care from relatives. ME/CFS is triggered by viral infections, among other things, and since 2020 also by COVID-19. Around one fifth of all people who suffer from Long COVID develop ME/CFS.
Knowledge gaps in the medical profession
Although the World Health Organisation (WHO) included the disease in the International Classification of Diseases (ICD) 55 years ago, there is still a great deal of ignorance. There is still no medication for the treatment of ME/CFS.
The German Society for ME/CFS and the LiegendDemo initiative recently criticised in an open letter to the associations of statutory health insurance physicians that there is no separate medical guideline in German-speaking countries and that ME/CFS is not explicitly included in the catalogue of medical learning objectives. According to the letter, knowledge about the disease among doctors is "inadequate".
A report by the Institute for Quality and Efficiency in Healthcare (IQWiG) in 2023 confirms this. For example, "the disease, its symptoms and diagnosis are often unknown to doctors and other healthcare professionals or are not sufficiently well recognised [...]".
What about drug candidates?
Large sums of money are now being channelled into research into ME/CFS. In mid-September 2023, the Federal Ministry of Education and Research (BMBF) announced that it would be funding research into the underlying disease mechanisms with 15 million euros. In mid-March of this year, the funding volume for the 6 BMBF funding activities launched to date in the area of long/post COVID and ME/CFS totalled 59.5 million euros. Together with the project to elucidate the immunological pathomechanisms of ME/CFS, this results in a total funding amount of 61.7 million euros.
The Federal Ministry of Health (BMG) plans to provide up to 81 million euros for healthcare-related research projects between 2024 and 2028. There are also plans to fund initiatives to improve the care of children and young people suffering from Long COVID with up to 52 million euros.
The lack of research funding for promising drug candidates is shown by the example of MDC002: an active substance that is intended to enable mitochondrial regeneration.
The physician and drug researcher Prof Dr Klaus Wirth is certain that he has discovered the pathomechanism of ME/CFS. He refers to the disease as an "acquired, self-replicating mitochondriopathy of the skeletal muscles." 6 years ago
years ago, the pharmacologist became aware of a publication by Prof Dr Carmen Scheibenbogen. Scheibenbogen, Director of the Institute of Medical Immunology at Charité University Medicine, Berlin, and of the Charité Fatigue Centre and one of the world's most renowned experts, had described so-called dysfunctional receptors in ME/CFS patients, a phenomenon that Wirth was familiar with from his research on the cardiovascular system. He got in touch with her. Since then, the two professors have written several papers together.
Impaired intracellular sodium-calcium exchange as a cause of ME/CFS
Together with Scheibenbogen, he has developed and published a disease model for ME/CFS. For their considerations, the two researchers combined findings from cardiovascular studies, exercise tests, muscle biopsies, magnetic resonance imaging (MRI) and electron microscopy with physiological knowledge from experimental research.
The decisive factor is a disrupted sodium-calcium exchange in the muscle cells, which overloads mitochondria with calcium and thus damages them. Once these are damaged, this - according to the hypothesis - further disrupts the cellular ion balance. In addition, inflammation disrupts the regulation of blood vessels throughout the body, which primarily affects blood flow to the brain. What is particularly complex is that every time a PEM is triggered in a patient, the pathological processes in the body are fuelled anew. According to Wirth, this creates a "vicious circle" in which the destruction of mitochondria continuously reinforces itself. With their disease model, Wirth and Scheibenbogen present the first comprehensive approach to how ME/CFS can develop as an independent disease as a result of various triggers.
It is not yet clear what really happens in the organism of those affected. Nevertheless, pharmacological and therapeutic strategies to combat the disease can be derived from the findings to date. Wirth is so sure of his cause that he - together with a partner - has founded the biotechnology start-up Mitodicure with the aim of developing a drug that cures ME/CFS patients. According to Wirth, the drug in the form of a tablet would break the vicious circle by eliminating the damage to the mitochondria and allowing them to regenerate. In addition, blood circulation in the brain and muscles would be increased. Wirth believes that a cure for ME/CFS is possible, as the key mechanisms that maintain the disease would be eliminated.
"The key assumptions that we made early on have been proven. Prof Scheibenbogen at the Charité was also able to show that sodium increases with her MRI study," says Wirth. This has "confirmed central assumptions of our model".
Not everything, of course, but a lot. For example, Wirth and Scheibenbogen's working concept clarifies why damage occurs under stress but not at rest. The frequently expressed assumption that antibodies play a role also raises the question: why does the damage occur under stress and not at rest? "Many things fit together very well. A drug that arises from a plausible hypothesis could provide proof that it is correct," says Wirth.
Acquired mitochondrial myopathy instead of ME/CFS
Safety and tolerability studies are now to follow: "We are on the way to a phase I study, which would then be followed by a phase II study," says Wirth.
The research phase on the effect of MDC002 has been completed. "We can't do any more, there is no animal model for ME/CFS." The plan is to have the two studies carried out by pharmaceutical service companies that specialise in such investigations. But this requires investors and venture capital. The problem is that there is no public research funding for innovative drugs.
Another start-up that is pursuing the approach of intercepting the autoantibodies is also not receiving any research funding. Why is that? We don't know exactly, says Wirth. It is possible that the prevailing view is that small biotechnology companies have to finance themselves. But perhaps it is also assumed that ME/CFS is not yet understood well enough and therefore a drug cannot yet be developed.
This is an understandable and initially plausible idea, says Wirth. Nevertheless, it is wrong. Many diseases for which effective medication already exists are far from being fully understood. In principle, it is right to first recognise the disease mechanisms and only then do something about them. "As soon as you have a reasonable working hypothesis, you should start researching it - and not only when the mechanisms of a disease have been definitively proven. We understand the disease well enough, now is the time to conduct drug research," explains Wirth.
By demonstrating the muscle disorder, Wirth and Scheibenbogen hope to get the frequent attribution of "psychosomatic" for ME/CFS out of people's heads. "We want to call the disease 'acquired mitochondrial myopathy'. If the power stations of the cells no longer function, you can survive, but you can't really live with it. You can hardly stand up, you can't walk, you can't work. That should make sense," emphasises Wirth.
Working concept increasingly confirmed by other research findings
Wirth and Scheibenbogen's disease model is increasingly being confirmed by other research findings. This began in early January 2024 with the findings of Dutch scientists. For the first time, they demonstrated structural muscle damage after muscular exertion in patients who had developed ME/CFS as a result of Long COVID, for which no capillary circulatory disorder can be held responsible.
This was followed shortly afterwards by a study from Ulm in which damaged muscle cell mitochondria were detected by electron microscopy, confirming the hypothesis of mitochondrial damage. A third study from the Scheibenbogen working group confirms the importance of skeletal muscles in ME/CFS. It shows that the strength of the hand muscles correlates with the severity of the symptoms and can be a marker in the early phase of the disease.
In their recently published review, Wirth and Scheibenbogen discuss the current state of knowledge about the key role of skeletal muscle pathophysiology. They conclude that "based on this pathomechanism", "future treatment approaches should focus on normalising the cause of the intracellular ionic imbalance."
