Mitochondrial treatments usually fail to make much of a difference in these diseases. Could a unique new drug – IVO-21 – be different?
Solve ME really hit it out of the park with their May 26th Catalyst Award, “Mitochondrial Stabilizer IVO-21 as Therapy for ME/CFS.”
We see different kinds of treatment options pop up from time to time, but this one is unique. Sometimes MD’s come up with possible treatment options and produce clinical trials. This is not surprising. After all, they have first-hand experience treating patients. You would think they would come up with new options.
As grounded as they are in the patient experience, however, they’re usually not researchers, and that makes a difference. Deeply embedded in the biology, researchers have analytical and statistical skills honed by the rigor of getting a PhD and succeeding in a research environment. They are a different kind of animal.
Dr. Jay Chung
Whoa! Another NHLBI mitochondrial researcher is studying ME/CFS!
Dr. Jay Chung is that kind of animal, and his IVO-21 drug comes from a different place than most of the drugs being trialed or considered for these diseases.
First, though, more about Chung – who has quite a resume. He has a bachelor’s degree in electrical engineering and computer science from MIT, an MD and PhD in genetics from Harvard Medical School, and an endocrinology fellowship at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
He’s currently a senior investigator and the chief of the laboratory of obesity and aging research in the National Heart, Lung, and Blood Institute (NHLBI). He’s won the James Tolbert Shipley Prize for excellence in research, the NHLBI Director’s Award, and the Orloff Scientific Award.
What all this means is that Chung’s insights into a potential therapy come with extra rigor. Doctors have an edge because they’re seeing how patients fare day in and day out. They’re seeing things from the outside in. Chung, on the other hand, brings decades of deep physiological understanding. He’s approaching ME/CFS from the inside out.
Like Paul Hwang, MD, PhD, Chung is an intramural researcher at the NHLBI, which historically has had almost nothing to do with ME/CFS. Interestingly, the first intramural researchers from the NHLBI to take on ME/CFS are both mitochondrial researchers.
Neither happened upon ME/CFS because of Nath’s intramural NIH study, which, in its limited testing, found no evidence of mitochondrial dysfunction. These NIH researchers came to ME/CFS on their own.
Dr. Chung’s Solve ME/CFS Presentation
Dr. Chung provided a most interesting start to his presentation. He went over the four immune hypotheses: viral persistence, viral fragments, autoimmunity, viral reactivation.
First, he mostly threw out the viral persistence hypothesis, then he discarded toxins, then he asserted that ME/CFS was probably not just a post-infectious disease…The man was on a roll!
He noted that antiviral, immune, and metabolic therapies have not proven out. A mitochondrial researcher, he pointed out that, thus far, mitochondrial and metabolic therapies (CoQ10, NAD+, acetyl-carnitine, D-ribose, metformin) have had pretty middling results.
The trigger doesn’t matter, he proposed, because ME/CFS and long COVID are occurring at a very deep level. They’re not just immune, or brain, or muscle diseases – they’re “cellular-stress” diseases – which means they can affect any part of the body that experiences too much cellular stress.
It all begins, Dr. Chung believes, with those tiny organelles that power our cells and ultimately our bodies – the mitochondria. Talk about deep – it all started over a billion years ago. Formed by the fusion of ancient bacteria and an ancestral cell type, our mitochondria differ from other organelles found in our cells.
Instead of the helix shape our DNA comes in, mtDNA – which came from an ancient bacterium – form a circle, causing the cells immune system to attack it. (Image from Wikimedia Commons National Human Genome Research Institute, Public domain. )
a title=”National Human Genome Research Institute, Public domain, via Wikimedia Commons” href=”https://commons.wikimedia.org/wiki/File:Mitochondrial_DNA_lg.jpg”>Instead of forming a helix, mitochondrial DNA (mtDNA) forms a circle. When mtDNA is released out of the mitochondria into the interior of the cell, it looks like the bacteria that it was – and, not surprisingly, provokes a reaction.
Chung is right on the bleeding edge of our understanding of how this happens. His 2019 paper, “VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease,” described how oxidatively stressed mitochondria release short mtDNA fragments into the cell, triggering interferon production (inflammation) and an antiviral response.
Since we clearly don’t want the cell to start battling itself, the question becomes: how does this highly virulent material (mtDNA) get from its happy place – inside the mitochondria – into where it’s not wanted – the cell?
Since mtDNA is highly disruptive, the cell has produced two membranes, the second of which is called the voltage-dependent anion channel, or VDAC, to prevent this from happening.
Usually, these VDAC channels are helpful and, in fact, play a crucial role in cellular function. They are channels through which ATP, ADP, and other factors move from the mitochondria into the cell interior (cytosol). When the mitochondria come under stress, from oxidative stress, calcium overload, etc., the proteins that make up the VDAC can form macro-pores, through which mtDNA can escape.
In Chung’s 2023 paper “Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway,” he described the (excruciatingly) complex biological pathways in the cell that produce the mtDNA-triggered inflammation. The paper noted that the macrophage-produced inflammasome “requires the release of oxidized mtDNA”. That finding alone, if I’m reading it right, would have mtDNA release driving a nice chunk of the innate immune response – which we pretty much know is overactivated in ME/CFS.
The authors concluded that uncovering this pathway produced a “paradigm shift” in how mtDNA may cause disease. They stated that “inhibitors of VDAC macropore formation, along with inhibitors of inflammatory pathways, could provide new ways to treat inflammatory diseases.”
When the mitochondria come under stress, the VDAC proteins can form macropores, which allow mtDNA to leak out of the mitochondria into the interior of the cell – provoking an inflammatory response. (Image from Dr. Chung’s Solve ME presentation).
The inflammatory process does not necessarily stop at the cell wall, however. If mtDNA is released outside the cell, it does the same thing it did inside the cell: it creates havoc. Called a “DAMP” (damage‑associated molecular pattern), it produces further inflammation. Several molecules (ATP, HSPs, etc.) are considered “DAMPs,” but mtDNA arguably produces the strongest reaction.
mtDNA – the Clotting Factor?
These escapees signal that cellular damage has occurred and immediately trigger an innate immune response. A 2026 review, “Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer” by Chung and company, showed how extracellular mtDNA release may play a key role in long COVID and ME/CFS by inducing platelet dysregulation and clotting.
Platelets are unusual. Lacking a nucleus and filled with mtDNA, they are prime innate immune system triggers. Because platelets are a major source of circulating mitochondria, they could be dumping large amounts of mtDNA into the bloodstream. That would surely trigger the innate immune response, stimulate neutrophils, encourage NET formation (remember the NETs?), and increase inflammation and clotting, and contribute to the microvascular problems, reduced muscle perfusion, etc., found in long COVID and ME/CFS (!).
IVO-21
Chung’s IVO-21 drug is a mitochondrial stabilizer that firms up the outer mitochondrial membranes (VDAC) to prevent mtDNA from entering the cell interior, causing inflammation, mitochondrial stress, and ultimately reduced energy production.
He’s shown in animal models that IVO-21 blocks mtDNA release and two cytokines, IL-6 and IL-1b, which he believes contribute to PEM.
Stopping inflammation/mitochondrial energy drain isn’t the only tool in IVO-21’s toolkit, though. IVO-21 is also able to enhance autophagy – the process by which damaged mitochondria are safely removed from the cell. Because damaged mitochondria produce inflammation and reduce energy output, the cell must regularly remove them (or recycle them, actually).
The damaged mitochondria are moved into a lysosome, which uses an acid bath to break them down and recycle them. Chung’s findings suggest that IVO-21 can enhance the lysosome’s ability to safely break down damaged mitochondria. Gunnar Gottschalk and Avik Roy of Simmaron have found reduced mitochondrial autophagy in MCFS. The ongoing rapamycin trials are trying to fix that.
The WASF3 Connection
It gets even more interesting – and connected. Health Rising recently covered Paul Hwang’s fascinating WASF3/ER stress finding, which could produce reduced mitochondrial energy levels across the body. Chung found that treating immune cells from ME/CFS patients with IVO-21 reduced WASF3 levels.
How it does this isn’t clear, but by reducing inflammation, IVO-21 may be relieving the ER stress Hwang believes is causing WASF3 levels to rise in ME/CFS.
Overstressed mitochondria could trigger inflammation by releasing mtDNA into the cell. The inflammation then disrupts the endoplasmic reticulum, allowing WASF3 levels to climb. High WASF3 levels then shut down mitochondrial antioxidant and energy production and produce more inflammation, keeping the vicious circle going.
Chung also found VDAC levels that were 2 1/2 times higher in ME/CFS patients. This doesn’t necessarily mean they were forming the macropores (VDAC oligomers) through which mtDNA escapes into the cell, but it does indicate that the mitochondrial membranes in ME/CFS were under stress.
The next steps would presumably be assessing whether VDAC oligomers or macropores are present, how much mtDNA is found in the cytosol of ME/CFS patients’ cells, whether increased mtDNA is found in the blood, and whether IVO-21 can reverse all of this.
Paradigm Changer?
Chung’s work potentially points to a new way to treat inflammatory diseases.
IVO-21 is not simply a drug Chung picked up off the shelf. He synthesized it in his lab to stabilize mitochondria and prevent mtDNA release. In their 2025 paper, Chung et al. proposed that IVO-21 could represent a paradigm shift in treating disease. Not many things could be considered paradigm changers, but Chung’s mtDNA concept and the production of IVO-21 could conceivably be.
Their 2026 IVO-21 patent application identified 25 broad disease categories which included over 200 diseases. They explicitly included diseases like ME/CFS, Long COVID, fibromyalgia, POTS, and other post-infectious syndromes in their application.
The patent application indicates that using cells or animal models, Chung has successfully tested in IVO-21 a wide variety of conditions, including T-cell exhaustion, thromboinflammation, kidney injury, heart failure, obesity/insulin resistance, and others. The fact that Chung has achieved strong results across such disparate areas of the body suggests he is targeting a core cellular process.
The diverse array of diseases aligns with how Chung explains the wide variety of symptoms in ME/CFS: he believes they arise in tissues where mtDNA-initiated inflammation occurs.
If mtDNA release is preventing autophagy from clearing out damaged mitochondria in the endothelial cells, for instance, problems with blood flows will result. If that’s happening in the brain, cognitive and other problems will result.
Because every cell in our body has mitochondria (except red blood cells), the potential range of damage is immense. Chung noted that mtDNA leakage could contribute to a leaky blood-brain barrier, a leaky gut, and even changes in the gut microbiome. (IVO-21 does cross the blood-brain barrier. In fact, Chung’s lab’s first target was neuroinflammation.)
When asked about emotional stressors, Chung noted that if an emotional stressor was tied to inflammation, it could cause mitochondria to rupture (leaking mtDNA). He reported that stress hormones have been directly linked to mitochondrial dysfunction.
Through the “Valley of Death” VO-21 Goes
IVO-21 got a big boost when the National Center for Advancing Translational Sciences (NCATS) gave it funding to assist moving it to clinical trials. Founded in 2011, NCATS mission is to speed the development of diagnostics and treatments.
Many potential new drugs die because they can’t make it through the “valley of death,” where new drugs need to undergo expensive animal and other testing before they can make it to human trials.
Depending on how much NCATS is involved in IVO-21, NCATS support could save millions of dollars in outside drug development costs, which would otherwise eventually be passed on to consumers, and it should speed up the process.
Still, it will take time. Comparing drug development to pregnancy, i.e., Chung said there are no shortcuts – it’s going to take time.
Because IVO-21 is a new drug, it will first need animal and toxicology testing (1-2 years), then phase I human safety trials (1 year), and then phase II human trials to assess efficacy and dose. It will take 2-3 years to reach human trials.
While we would all love for things to move more quickly, IVO-21 will benefit, however, from being embedded in a rigorous testing environment. We will learn a lot about it.
Solve ME’s Crucial Role
If NCATS is already involved, what is Solve ME funding? NCATS is supporting general drug development, but Solve ME is funding testing of IVO-21 in ME/CFS mouse models to determine if the drug improves energy production and reduces inflammation. Solve ME is essentially betting that IVO-21 will make it through the toxicology testing phase (Chung thinks it will), and that when it does, Solve ME’s proof-of-concept trial in an ME/CFS mouse model will give it a leg up in human trials.
Cost
The webinar did not address one of the potentially remarkable and helpful things about this drug – its putative low cost.
The patent application – which explains how the drug is synthesized – may provide a clue. Chung worked on this drug after experimenting with azole-type antifungal drugs such as ketoconazole. Although none worked, he got the idea to synthesize a new azole-type drug.
Because IVO-21 is a synthetically produced small molecule, instead of an antibody, protein, gene therapy, cell therapy, or other biologic, it should be considerably less expensive to produce it. The chemicals needed to produce IVO-21 are not rare and do not appear to be particularly expensive. The drug appears, at least for now, to work in low doses, and the ability to take it in pill form also cuts costs. Plus, as noted, NCATS is shouldering at least some of the development work needed to bring the drug to market.
Time will tell when and if IVO-21 actually gets to the manufacturing process, however, how expensive it ends up being.
Remarkable Possibility
We don’t know whether macropores are leaking mtDNA into ME/CFS patients’ cells, or whether IVO-21 will pass its toxicity tests, but the drug seems to present a remarkable possibility given the potential IVO-21/WASF3 connection.
What I particularly like about this drug regarding ME/CFS is its rich biological background and the extensive testing it will receive. Because it appears to be getting excellent funding and comes out of an extensive research framework, one way or another, we should know yea or nay on it. (In other words, IVO-21 is not going to be Ampligen (!).)
What a remarkable coincidence that two intramural mitochondrial researchers working in the same NIH institute – but focused on different areas (aging/cancer) have become interested in ME/CFS. Even more unlikely, their work may very well coincide! IVO-21 could be the answer to WASF3, and WASF3 could help explain why mtDNA is having such an effect.
This is the kind of synchronicity we should expect to see more and more. As we learn more about ME/CFS, more researchers will be drawn to it (even from Institutes like the NHLBI), and more of these unexpected synchronies will show up. When senior researchers like Chung and Hwang out of the blue get interested in ME/CFS, you know we’re making progress.
Solve ME Board Member Mary Riew was the spark behind the Chung grant. 🙂
The intersection of these two researchers suggests that while ME/CFS may be unusual in some ways, it isn’t the outlier some have made it out to be; it shares biological pathways with other diseases, and that’s how we get hooked into potential treatments.
As so often happens in medicine, serendipity also played a role. Serendipity showed up for ME/CFS and Hwang when a woman in a family he was studying to learn about cancer happened to have it. It showed up for Chung during a wedding when Solve ME Board member Mary Riew talked with Dr. Chung about his work and encouraged him to apply for a Catalyst grant. You never know what may happen when you share about this disease. We can thank Mary for getting Chung involved, and Solve ME for funding this fascinating grant.
(It was a good year for the Catalyst grants. The “Sequence ME & Long Covid” grant, which helped DecodeME expand its whole-genome ME/CFS project, was another knockout!)
