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NIH ME/CFS Advocacy Call – May 1, 2023
Barbara McMakin: Good afternoon, everyone. My name is Barbara McMakin and I'm from the NINDS Office of Neuroscience Communications and Engagement. On behalf of the NIH, I would like to welcome you to this afternoon's call and to thank you for your interest in participating in this discussion with us today.
Today's call is being recorded. If you have any objections, please disconnect at this time. Unfortunately, Dr. Koroshetz has a conflict today and can't join us for this call. Now after some updates from NIH, Dr. Vicky Whittemore will introduce the guest speakers who will give a presentation on their recent work. Then we will open the webinar to questions.
During the Q and A session, if you have a question for our speakers, please select the Raise Hand button at the bottom of your Zoom screen and we will call on you to unmute. If you are joining us by phone, please dial star 9 to raise or lower your hand and star 6 to mute and unmute. You can also submit questions using the Q and A box at the bottom of your screen. We will try to make our remarks brief so that we can answer as many questions as possible in the time we have available to us this afternoon. Now I would like to hand the call over to Dr. Vicky Whittemore.
Dr. Vicky Whittemore: Thank you, Barbara. Good afternoon and welcome to the second NIH ME/CFS call for 2023. Since our last call, there have been several developments and NIH related activities on regarding ME/CFS. And we look forward to sharing all of those updates with you.
I'll start with updates on the activities of the Trans-NIH ME/CFS Working Group and then turn it over to Dr. Nath, who will give updates on the intramural ME/CFS studies and other studies ongoing in intramural at NIH. Then Dr. Joe Breen from NIAID will update us on the Collaborative Research Centers and Data Management Coordinating Center and talk about the upcoming NIH conference that planning is underway for. And then we'll have two guest speakers who I will introduce. So we're pleased to have Drs. Gunnar Gottschalk and Avik Roy, who I'm pleased to announce were just awarded an NIH R21 research grant award last week. Congrats to both of them and thanks for being here.
So first, I'd like to update you on the process we're going through to develop an NIH ME/CFS Research Roadmap. The goal of this roadmap is really to assess the state of the research and to determine what we know, what we don't know and identify gaps in the research that will really help to drive the research toward clinical trials. So it's as everyone knows, and is well aware, there are no FDA-approved treatments for ME/CFS. And so what we would like to really focus the research priorities that come out of this research roadmap on are what is needed to really get to clinical trials that we can develop new treatments and FDA-approved treatments for ME/CFS.
So we have invited and appointed individuals to serve on the NINDS Working Group of Council and this group is made up of several clinicians, investigators, as well as leaders of the ME/CFS advocacy community, as well as five individuals with lived experience. So they're either individuals who themselves have ME/CFS or are caregivers for individuals or an individual or individuals with ME/CFS. In addition, through a self-nomination process where we were quite overwhelmed with a large number of applications, which was really fantastic, to have so many people interested in participating. We identified 27 additional individuals with lived experience and again these are caregivers or individuals with ME/CFS to also participate in the process and they'll be helping us to organize and carry out several different webinars that will be open to the public on different topics in areas of ME/CFS research and those webinars will be open to the public. And we're, like I said, just in the initial planning phases of the first webinar that we hope to have scheduled sometime in June. So we certainly will make the community aware of the date and information about that webinar as soon as it's available.
There will be ways for and all of you who aren't actually part of this process already to participate. So as I said through the webinars, and we're also going to use a crowdsourcing tool called IdeaScale to gain additional input from the community on the research priorities. Because after each of these webinars, the group will develop research priorities from the information that's gathered, by listening to subject matter experts at the webinar to put out research priorities for that area. So we'll be looking for additional feedback from the community. And then a draft report will come out at the end of 2023 to be presented to NINDS Council in February of 2024.
I also want to share that we've awarded a grant for the NIH Center for Collaborative Research at Cornell University and are close to issuing the award for the Data Management Coordinating Center. We also reissued a funding opportunity and it's our intention to fund an additional two Collaborative Research Centers, and the deadline for those applications is mid-June, June 16th. We're also in the process of organizing a young investigator meeting that will take place the day before the NIH research conference, which Dr. Breen will talk about later. The young investigator workshop and the conference will be both in-person and virtual, and so we're still working out the details for both of those, but again, we'll let you know as soon as the details are available for those meetings. With that, I'd like to turn it over to Dr. Nath.
Dr. Avindra Nath: Thank you, Vicky. So I'm pleased to share where we stand on our studies with regards to ME/CFS. So as you know, we conducted a very comprehensive, large study here intramurally and it was not an easy task to put it all together and to even write it because there were so many different disciplines involved. We've now put it together and the manuscript has been submitted, it's currently under review. So that will have explicit details on everything that we did to this population. However, everything cannot go into a single manuscript, so there'll be several other manuscripts that are going to come out. Each one of them is going to take a piece of it and then describe it in more detail. So a second manuscript on muscle alone has already gone out and is under review, and then there will be one on microbiome and so on and so forth. So there's going to be a whole host of manuscripts coming out as soon as the first one gets accepted for publication. We're also keen on trying to see, based on these observations, that we should try to conduct some pilot clinical studies, clinical trials here at NIH. So those things are currently in process of discussion.
We've done a lot of work on Long COVID over the last three years, and we've submitted several manuscripts that have already been published. One describing peripheral neuropathies, one transverse myelitis, two major manuscripts on the neuropathology of COVID, one on cognitive aspects of Long COVID that is currently in press. We just saw the proofs yesterday. And we've written lots of reviews, editorials, shared the information with the public and scientific organizations. We've organized workshops on the topic that include ME/CFS and Long COVID. So we tried to get the community engaged the best that we can.
Now, we've also initiated a study on Gulf War Syndrome and those patients have started coming in. And lastly, we also have a clinical trial for Long COVID using IVIG, and so we're currently recruiting patients for that study. So I'll stop here. Thank you.
Dr. Vicky Whittemore: Thanks. Over to you Dr. Breen.
Dr. Joseph Breen: Thanks, Dr. Whittemore. Hi, my name is Joe Breen and I'm a program official in NIAID and work closely with Vicky and others in NINDS on the NIH-wide ME/CFS Working Group. And I want to report a little bit of the progress that's occurred in the Collaborative Research Centers since we last spoke about them at the last telebriefing.
There really are two major areas that I want to talk about. One is papers that came out actually at just about the same time as the last telebriefing. And these were two studies that were done by the Columbia group led by Ian Lipkin and also the Jackson Lab group led by Derya Unutmaz and Julia Oh that really ended up characterizing the gut microbiome from ME/CFS patients and healthy controls and showed that there were significant differences in butyrate-producing capacity. Both papers in fact found the same as well as different bacterial species that differed.
But what was nice is that it was validating, and it happened in two Centers, both were reported independently in Cell Host and Microbe, but I think it lends more evidence to the metabolic disturbances as well as helps to highlight some of the pathways that could potentially be intervened in a clinical study, for example. And I think something that was lost in some of it was the phenotypic, and microbial and even metabolic biomarkers that come out of these studies, which in a research setting I think will help direct future work.
Coincident with these reports actually, the Center led by Dr. Maureen Hanson at Cornell had two papers that I want to talk about. One was published very recently in March, Geoff Moore is the first author, looking at, really, post-exertional malaise in ME/CFS subjects and healthy controls and this was a study of actually a significant number of patients, 80 patients and 64 healthy controls, showed that after two-day exercise testing, those with ME/CFS took about two weeks to recover whereas healthy controls took two days. Now this is interesting for a few reasons. It may help us use a quantitative measurement of PEM, which could actually end up helping design strategies to manage, but also knowing this kind of information can be really helpful to inform people who go into future studies and in terms of what outcomes can be expected. So I think we can't broadly over-interpret it, but I think it was a really unique finding. And the other unique finding from the Hanson group is a study that's a small pilot but showing that there were differences in urine metabolism between female ME/CFS patients after maximal exertion versus healthy controls. I think that's also very interesting. It's obviously a readily accessible fluid for biomarker studies etcetera. Something that isn't a pilot scale but I'm sure is being followed up.
The Collaborative Research Network, as Vicky mentioned, has a Data Coordinating Center and they published a paper in 2021 showing their mapMECFS tool and I would encourage folks to return to that website because they are really working hard and adding new data and really increasing the power of that tool as part of the Data Management and Coordinating Center function. I think I'll stop there.
I think that's the general progress for the CRCs, and I just wanted to follow up that the NIH Working Group is planning on a meeting in 2023. It will be in December, December 12th and 13th, on campus. Really as a follow up to the 2019 meeting, this will be a way to talk about the status of ME/CFS research, but also to link it to potential interventions based on pathways which have been discovered since 2019 and subsequent, and also leverage to the extent possible and learn what we can from Long COVID. There's an organizing committee that's creating an agenda and we're very thankful to have co-chairs Drs. Nancy Klimas and Andrew Grimson. As soon as the agenda is public, of course we'll share that and again like Vicky mentioned, it will be a public meeting and also hybrid. So while we'll have it on campus it should be available wider as well. Over.
Dr. Vicky Whittemore: Thank you very much, Joe. So I see a couple of people have hands up. We're going to take questions after we hear from our guest speakers. So not that we're ignoring you, we see that your hands are up, but we'll start the question and answer period after we hear from Avik and Gunnar.
It's my pleasure today to introduce Dr. Avik Roy who's the Chief Scientific Officer at Simmaron Research, Inc. and Dr. Gunnar Gottschalk who's the Executive Director of Research at Simmaron Research. And as I said earlier, we're thrilled that NINDS has just issued a research grant award to Gunnar and Avik entitled “ATG13: A new player in ME/CFS”. And so we're very pleased to have you both today and I'll turn it over to you for your presentation. Thank you both.
Dr. Gunnar Gottschalk: Hello everyone. Thank you so much for the invitation from NIH. My name is Dr. Gunnar Gottschalk. It's so wonderful to be here, to share some of our recent work, and to introduce what our plans are moving forward in the next couple of years.
Simmaron Research is a 501(c)(3) non-profit biomedical research institute. We have and really try to focus on multidisciplinary translational science. We collaborate directly with Dr. Dan Peterson at Sierra Internal Medicine where for many years we've worked and collected samples and executed clinical trials in Incline Village, NV. Our more recent change has been to bring and start the Simmaron Research and Development Laboratory, which is based at the University of Wisconsin, Milwaukee campus. And our primary focus there is to translate some of the findings from the Incline Village and other clinical collaborations into the laboratory and that includes looking at biomarkers and animal models as well as drug discovery. A huge benefit of our spot at University of Wisconsin, Milwaukee is we are also a part of the Milwaukee Institute for Drug Design. So that is a group, essentially a group of chemists, that is focused on drug development in multiple different types of disease settings. And so while we're very much new to the UWM system and certainly chronic fatigue syndrome, ME/CFS is very new to the UWM system. We're extremely excited to be there and leverage opportunities to try to find new mouse models, new cures, etcetera.
This is our team. You'll be hearing from Dr. Avik Roy who's the Chief Scientific Officer following this. Of course, Dr. Daniel Peterson is still the Clinical PI at Sierra Internal Medicine and I am myself, as well as the Executive Director, a Principal Investigator.
We have two primary focuses coming up in 2023 that Avik will get into in a moment looking at mTOR activation and autophagy impairment. We've published a manuscript looking at the target ATG13, which is a very important molecule for the induction of autophagy. Autophagy is a process in the cell that helps remove specific types of proteins from intracellular waste products and that is one of our projects.
And then secondarily, we're trying to translate that finding of autophagy impairment in ME/CFS patients into animal model development, specifically looking at cardinal symptoms of ME/CFS. I want to preface this by saying we're not trying to make a mouse model to understand all of ME/CFS. That would be impossible. Our primary focus is to look at cardinal symptoms, including post-exertional malaise. We feel that in other fields of neuroscience including Alzheimer's disease and Parkinson's disease, there has been a lot of progress made with respect to drug development and the understanding of illnesses through animal models, and that's what we plan on doing. And specifically because both Avik and myself have a background in Parkinson's disease and Alzheimer's disease, we felt that it would be a wonderful contribution to this field.
We, like Vicky said, we're very thankful for the R21 funding. We've also had support from the Solve M.E. Ramsey Award Program grant, which is another competitive grant award system and also through our local connection to the Parasol Tahoe Community Foundation. And finally, a thank you to all of the donors who also support our work. Thank you so much. And with that, I'm going to turn it over to Dr. Avik Roy and he's going to talk about our current progress. Avik.
Dr. Avik Roy: On behalf of Simmaron Research, I would like to say thank you to NIH for this opportunity. Today, I'm going to talk about our ongoing research. It's in very pilot stage right now, how mTOR activation and subsequent autophagy impairment are critical in the context of ME/CFS. So let's start with some background.
ME/CFS is a chronic, multi-system illness characterized by severe muscle fatigue, pain, and brain fog. Cardinal symptoms of this disease are post-exertional malaise, which is a severe fatigue, pain and dizziness post-treadmill exercise and orthostatic intolerance, which is characterized by sudden drop of blood pressure while maintaining the upright posture. Despite intense investigation, until now, the molecular mechanism of this disease is poorly understood.
However, there are some potential contributing pathways that are believed to be involved in the pathogenesis of ME/CFS. Some of these are mitochondrial toxicity of regulation of inflammatory molecules, myelin abnormalities, and autophagy impairment. The challenges that impede the understanding of this disease are lack of sufficient post-mortem biospecimens. This disease is highly heterogeneous in nature in terms of its etiology and there is no reliable disease model. So our goal is to make a disease model to study some of the pathological features of ME/CFS. In our context, it is post-exceptional malaise. So we want to achieve this goal by three different strategies.
The first one is a drug induced animal model in which we will administer drug in a mouse to induce PEM. The second is a transgenic mouse model, where we manipulate a host gene to induce post-exertional malaise and number three is a disease-relevant model where we want to induce a virus or a plasma-infused mouse model.
So let's talk about a drug-induced mouse model first because this is the study we are doing right now. So the targeted pathway is autophagy. Let's give a brief background of autophagy. Autophagy is a cellular quality control process by which the defective mitochondria and biologically inactive proteins are enclosed in a vesicle known as autophagosome and then targeted to lysosome for further hydrolysis. So if you look at the entire process, you can see that there are multiple proteins are involved in the process in different layers. And many of these proteins are tightly connected in disease and regular health. For example, Beclin and LC3-2, these two proteins are reported to be up-regulated in the serum of patients with acute ischemic stroke. Beclin and p62, these two proteins are upregulated in the serum of patients with pulmonary embolism. ATG5 has been reported to be upregulated in Alzheimer's patients. Alpha-synuclein is reported to be upregulated in Parkinsonian patients. So many of these proteins are upregulated in serum during different metabolic disorders. However, the role of this pathway, autophagy and its impairment, is not studied well in ME/CFS.
To understand the autophagy impairment in ME/CFS patients, we performed an antibody array. Antibody array is a procedure in which a membrane is engraved with antibodies of different metabolic proteins. So in this, the membrane is engraved with 34 antibodies of 34 different autophagy-related proteins. And after that, the membrane is challenged with the serum of healthy control and patients. So we have two different representative images. These are collected from two different case control studies. The first one is an age matched and gender matched healthy male and patient and the second one is age and gender matched female patients and healthy control. So in both cases, you can see that the many proteins, there are lot of autophagy-related proteins that are upregulated in patient serum. However, the ATG13, which is shown in this rectangular enclosure, in both cases is consistently upregulated. So we are intrigued about the upregulation of ATG13 in patient serum in ME/CFS patients.
So subsequently we performed an ELISA study in 10 different cases, 10 healthy controls and 10 age matched patients, and we saw that ATG13 is consistently upregulated in the serum of all ME/CFS patients. We further continued to understand the metabolic regulation of ATG13 and we did immunoblock studies where we found that ATG13 is heavily phosphorylated in its serum residue and that phosphoserine is strongly elevated in patients, in ME/CFS serum. So we further continue to show that that ATG13, when it is phosphorylated, it’s become inactive and it goes to the serum of ME/CFS patients and it also can induce ROS and nitric oxide production via RAISE-mediated induction of iNOS.
We published this piece of work in Molecular and Cellular Neuroscience last year. But our current study is just after that, it starts just after that. So until now we know that ATG13 is inactivated and when it gets inactivated it becomes phosphorylated and it is elevated in the serum and it causes autophagy impairment. And that subsequently causes the other downstream metabolic disorders, such as mitochondrial dysfunction, cell death, and inflammation. But we really don't know what causes ATG13 inactivation. So what is the upstream molecule that causes ATG13 inactivation?
Then we looked at the signaling pathway and we found that there is a, there is a cytosolic protein. Its name is mammalian target of rapamycin or mTOR, it's a kinase. It's a serine/threonine kinase and it has a dual role in the cell. So when it gets inactive then ATG13 can participate with the autophagy and that is a very integral process for a healthy tissue. But when mTOR is active, then it phosphorylates ATG13 in multiple serine residues. That causes the inactivation of ATG13 and ATG13 eventually aborts that active complex formation and that causes autophagy impairment. And we also hypothesize that mTOR, since it's the kinase, can regulate many downstream pathways that can induce different inflammatory molecules in the muscle tissue. For an example, IL6 and RANTES, and that might contribute to the pathology as well. And we want to test this hypothesis by this compound, and we have a code name that's SIM501. SIM501 is a potent mTOR activator and we want to see what happens if this compound is administered in a mouse.
So we took three different doses like 2, 5, and 10 milligram per kilo body weight and we administered this drug in mouse via gavage via oral route for 14 days, and after 14 days we planned to measure muscle fatigue through EMG measurement, post-exertional malaise pre- and post-treadmill regime, and we also want to see the attention deficit and brain fog in this mouse. Interestingly, after five consecutive days of feeding, we saw there is severe weakness in young female mice. So these female mice, they show severe fatigue with periodic episodes of freezing, their movement is slow, and at the end of 14 days of feeding they show a severe loss of their movement, severe fatigue, and hypothermia. We are going to the next slides where we can discuss more about this.
After 14 days of feeding what we found was that the young female mice, they didn't gain body weight and they have sufficient loss of muscle mass. And when we performed the EMG analysis we saw that the SIM501-treated mice display a certain pattern of muscle wave, which we call that marching soldier muscle wave and that kind of muscle wave is seen when there is inflammatory demyelination in muscle tissue. So muscle tissues are getting innervated by different peripheral nerves so when there is a demyelination in these nerves then we see this kind of muscle wave. Whereas for the vehicle-fed mice, we see a normal or a regular kind of muscle wave here, and we also measured grip strength and what we saw was that increasing doses of SIM501 caused a severe loss in grip strength. We also measured overall movement in the mice and we saw that SIM-treated mice they have shown a significant loss of their movement with periodic freezing.
Now we wanted to see the molecular evidence, like what exactly is happening in the tissue level. So we performed an H&E staining just to see a mononuclear infiltration in the tissue and we found that in bicep muscle in those mice, there is severe infiltration of mononuclear cells. And when we performed or characterized what kind of T cells or what kind of mononuclear cells are infiltrated, we did not see neither CD4 nor CD8 T cells there in the muscle parenchyma. However, we observed that there is a severe infiltration of macrophages in the muscle tissue after SIM treatment.
We further characterized those macrophages because there are two different types of macrophages. One type of macrophage is inflammatory and toxic, we call them M1 macrophages, and the other macrophages are called M2 macrophages which are protective and they are anti-inflammatory. What we found is that those infiltrated macrophages they have expressed CD40, which is a marker of M1 type of macrophages. So those macrophages, they are inflammatory macrophages and so we are characterizing more on these cells. So this is what actually I can share with you right now.
The next question we asked was whether these mice can show post-exertional malaise which is a very key pathological hallmark of ME/CFS. So to do that we let this mouse run on a treadmill. So this is before or pre-treadmill activity of these mice for the vehicle and SIM-fed mice and we can see that vehicle-fed mice are totally active and do not have any kind of movement deficit. Whereas SIM-fed mice have a partial movement deficit compared to vehicle-fed mice. However, when we make them run on a treadmill for 14 rpm per 15 minutes, immediately after that both vehicle- and SIM-fed mice have a transient fatigue that is quite expected. However, these mice have more fatigue immediately after the treadmill exercise.
Then we gave them two days of rest and after two days we saw that the vehicle-fed mice completely regained their movement whereas the SIM-fed mice are still very much inactive, and they still have movement deficits. So this is very intriguing and a very interesting finding actually, what we found so far and we are doing more molecular studies on that and on this mouse. So what kind of inflammation is happening and is there any inflammatory demyelination in the muscle nerves? So all these analyses are going on right now.
But what I can say is that there are some limitations of this drug-induced model because the fatigue is transient, because those mice they come back to the normal schedule after like one month. And the direct role of ATG13 is not clear in this mouse because the drug SIM can inhibit different other targets that we don't know.
To nullify these drawbacks, we plan to do an ATG13 knockout mouse model and we are expecting that the fatigue will be much more stable and we can at least establish the direct role of ATG13. But on the other hand, the ATG13 whole-body knockout mouse also show some kind of growth deficit, cardiomyopathy, and less viability. So this might confound the understanding of ATG13 or ATG13's role in ME/CFS.
So that's why we just applied and got a recent R21 NIH grant from NINDS where we want to make some kind of tissue-specific knockdown of ATG13 with this system, the Cre-Lox system. We will do muscle-specific mutation of ATG13, brain-specific and peripheral nervous system specific knocking down of ATG13. So what do we expect? We expect that ATG13 knockout, the ATG13 muscle knockout mouse will show some fatigue maybe some post-exertional malaise. But in the ATG13 brain knockout mouse they might show some kind of anxiety and attention deficit and the ATG13 PNS knockout mouse, they might show some sort of dysautonomia. So that is our expectation, but time will say what will happen in next few months or in a few years.
And so thank you all for your attention and this is our whole team of our animal study. Our Executive Director Dr. Gunnar Gottschalk and this is Dr. Leggy Arnold from University of Wisconsin, Milwaukee. Linda is our attending veterinarian who is helping tirelessly in our animal studies. And our collaborators are University of Wisconsin, Milwaukee and Coppe Laboratories and our current study is being funded by Solve M.E. and NINDS. So thank you all for your attention, thank you.
Barbara McMakin: Great thank you so much for that excellent presentation. We will now transition to the question and answer session and open the call for your questions. As a reminder, if you have a question for our speakers please select the raise hand button at the bottom of your Zoom screen and we will call on you to unmute. If you are joining us by phone, please dial star 9 to raise or lower your hand and star 6 to mute and unmute. You can also submit questions using the Q and A box.
We will start by taking questions for Drs. Roy and Gottschalk and I actually saw a couple questions for them in the Q and A box, so we can start there. Dr. Roy, can you say more about mitochondrial toxicity, potential causes and consequences and how it might trigger ME/CFS?
Dr. Avik Roy: Yeah, so mitochondria is our energy house that produce a lot of energy molecules known as ATP or adenosine triphosphate. When there is a mitochondrial toxicity, the first thing that will happen is less production of energy molecules ATP and that can cause a very fundamental toxicity in a cell system. So mitochondria are present in almost all types of cells in heart, in brain, and also in muscle cells. When there is less ATP production, when there is less mitochondrial function, then we also expect when there is mitochondrial dysfunction, there will be production of reactive oxygen species in the system. So that can trigger cytotoxicity, cell loss, and inflammation in the system. So if you look at inflammation, that is directly involved in the mitochondrial toxicity and the loss of energy also is involved in the mitochondrial toxicity. So these factors, they're very integral in the survival and growth and the function of any kind of tissue. So that's why mitochondria are very critical. Mitochondrial health is very critical in health and disease.
Barbara McMakin: Great. Thank you. Another question for you, why not consider an inducible knockout model?
Dr. Avik Roy: Can you repeat the question again?
Barbara McMakin: Why not consider an inducible knockout model?
Dr. Avik Roy: Yeah, that's what we are actually planning to do. The Cre-lox system that is the inducible knockout model. So we will inject the mouse with a drug named Tamoxifen. So when we inject the drug then the Cre-lox recombination happens and the ATG13 will be knocked out specifically in an adult mouse and it can be induced by the drug. So that particular model is very effective in order to nullify all the correlative deficits. We definitely have a plan to do that.
Barbara McMakin: Great, thank you. And can you talk about how the study in mice can possibly lead to treatment options for people with ME?
Dr. Avik Roy: Once we establish the disease model, our next target will be to cure that disease with the application of different drugs. And those drugs they can modify different metabolic pathways. One of them definitely is autophagy, so autophagy-related proteins. mTOR is a target. mTOR is one of our targets and we want to treat those disease models with some mTOR manipulator or mTOR modulator that can eventually ameliorate the disease progression and that can improve the pathology or that can protect the pathology.
And the second option we also tried to develop a type of therapy, some type of peptides that also can interfere in different inflammatory pathways in this disease model so that it can improve the disease pathology, it can protect the disease pathology. That's what our plan is. So definitely the next step is to design some drugs to prevent this kind of disease progression in a mouse. And after that we will go to the preclinical stage and definitely, we have a long plan after that.
Barbara McMakin: Great. Thank you. I see several people have their hands raised. Scott Daniska, go ahead and unmute.
Scott Daniska: Hi, yes. Can you hear me? Hi, so I wanted to ask, thank you for all your presentations first of all and Avik your analysis on autophagy was really interesting, but one of the things that you mentioned is a question that you left is what it what is the trigger for these changed or for these altered levels? And so I'm wondering if there's been thought as to underlying drivers of CFS and what can be done to look for these underlying causes?
And so there's been, you know, a lot of talk about hidden viruses, things like that, but a lot of patients, myself included, complain of things like toxic mold, VOCs in homes, renovations, etcetera, triggering a lot of their symptoms. And so I'm wondering if there's any thought or prospective studies that you can think of to begin to analyze the environments that people with CFS are living in and be able to correlate, for example, household products with emergence of CFS to really find an underlying driver? Thank you.
Dr. Avik Roy: Thank you so much Scott for your question. As I mentioned before that ME/CFS is a highly heterogeneous disease. So in terms of its etiology, it's very heterogeneous and it's really hard to say what exactly causes this abnormality. However, we have to start from something, from some common reference point. And as a molecular biologist we can target only a pathway in a cell, and we can start from that reference point. So if that pathway is modulated or if that pathway is manipulated, what are the consequences that can happen?
And from our preliminary study, from our pilot study we saw that ATG13 is a protein which is severely, or the metabolism of that protein is severely impaired. So that gives us an indication that the autophagy impairment is very critical in the progression of this disease. And yes, autophagy is a pathway that that is linked to all different sorts of metabolic pathways like inflammation, mitochondrial toxicity, apoptosis, all different things, all different metabolic processes. So right now in our understanding, the inter-pathway or the intermediated autophagy pathway is a very common reference point from where we can start our disease model study and where we can manipulate that particular pathway to understand and to identify a drug candidate and really it's very hard to say what exactly is causing the autophagy impairment.
Yes, you are right because you said that mold or having an infection. Yes, that might be involved, but as I said it's highly heterogeneous in nature and it's very difficult to say what exactly causes that autophagy impairment. So that's my understanding.
Barbara McMakin: Great, thank you. Deborah Duricka, please unmute and ask your question.
Deborah Duricka: Great. Can you hear me? Hi there, Dr. Roy you already answered my question. I asked why not use an inducible model before you mentioned Cre-LoxP? So that's it, thank you.
Barbara McMakin: Thank you. Cort Johnson, do you want to unmute and ask your question please?
Cort Johnson: Yes, thank you. Hi, Avik.
Dr. Avik Roy: Hi Cort, how are you?
Cort Johnson: I'm good. So with regards to I thought the macrophage infiltration into the muscles was so interesting. Could you do a muscle biopsy or something like that in ME/CFS and see if the same thing is happening?
Dr. Avik Roy: I'm glad to do that, yes.
Cort Johnson: Good, good, good, good. And with regard to mTOR inactivating drugs, what drugs, are there mTOR inactivating drugs available now?
Dr. Avik Roy: Yes, so rapamycin is one of them.
Cort Johnson: Okay, good, good.
Dr. Avik Roy: But again it depends on what stage of the disease and in my case when I did my pilot mouse study, we saw that young female, so we started with two different age groups. One is 3 to 4 weeks old mouse groups and another is the 5 to 6 weeks old mouse group. And what I found was that 3 to 4 week old animals, only female mice, are susceptible to the mTOR activation-mediated muscle fatigue, whereas 5 to 6 weeks old female mouse didn't show any kind of pathology after mTOR activation. So young female mice are more susceptible for this kind of model.
Cort Johnson: Got it, interesting.
Dr. Vicky Whittemore: If I can jump in, studying muscle biopsies from individuals with ME/CFS is part of the new funded Cornell center so you'll probably be seeing they'll be recruiting individuals for those studies soon. So I know that's part of their plan, upcoming plans.
Avik Roy: Can we have some muscle tissue from them if we want to?
Dr. Vicky Whittemore: I'll put you in touch with them. Yep.
Dr. Gunnar Gottschalk: Yeah, we'll figure it out.
Barbara McMakin: Great, thank you. There's another question in the Q and A box, will you also be looking for changes in sensory hypersensitivity?
Dr. Gunnar Gottschalk: Avik I can maybe take that. I think one of the beauties of the Cre-LoxP model with the tissue specific knockout of ATG13 for example, or any other target, is that you can target specifically neurons only or peripheral nervous tissue only or muscle tissue only. Those phenotypes that are described there, hypersensitivity etcetera, in neuroscience and other places they're pretty well described in animals to some extent. But again, we are dealing with mice, not humans. So we're going to do our best to see if we can develop and find some phenotypes that may be corollary marked towards what we see in human patients as well.
Barbara McMakin: Great. Thank you. Okay, Ruhi Snyder, please unmute and ask your question.
Ruhi Snyder: Hi, can you hear me?
Barbara McMakin: Yes.
Ruhi Snyder: Thank you so much. I really appreciate it. I just want to focus on demyelination a little bit. You're talking about demyelination of the muscles as well as I think from my research that I'm gathering is demyelination within the brain itself, so the white matter. My concern, my deep concern is the fact that the young humans who are suffering now from ME/CFS and this is an incredibly important time in terms of their brain development, especially in terms of myelination. And is there anything that we can do at all at the moment to stop that kind of process that is being generated because of demyelination that's happening both in the muscles as well as in the brain?
Dr. Avik Roy: Yes, so if you look at the CNS demyelinating diseases like multiple sclerosis and ALS, amyotrophic lateral sclerosis, all these diseases they have multiple therapies and so those are available. So you can definitely consult with any specialist in multiple sclerosis if you are interested in learning about demyelination. Any clinician in multiple sclerosis or expert in multiple sclerosis and ALS.
And in our previous research we have shown that cinnamon, which is a herbal spice we usually use in our curries and all these dishes, is very important that prevents demyelination or that protects myelin loss at least in our mouse model studies. And we also have initiated clinical study, a clinical trial in Ross University Medical Center in Chicago where actually a large number of patients, MS and ALS patients, were recruited in that study and the study is going on right now, the cinnamon treatment. And so that's what I can say, yes.
Barbara McMakin: Great. Thank you. We do see somebody who is calling in on the phone with their hand raised, the phone number ending 125, you can go ahead and unmute and ask your question please.
Eileen Holderman: Yes. Hi, hello. My name is Eileen Holderman. I'm an advocate and former member of the advisory committee to HHS in Washington. I'd like to thank everyone for the call and their presentations. My question, my comment and question are for Dr. Nath.
At the beginning of your NIH intramural study, the criteria for recruitment changed six times and we brought that to NIH's attention. So my question is did you use the experts definition or criteria, the MEICC? If not, why not? And can you comment on the extreme concern advocates are having over the criteria issue? Such as the creation of SEID by the IOM and the coding, recent coding of that on par with ME and the trend towards studying and focusing on one symptom of this vast disease, which is PEM? Thank you.
Dr. Avindra Nath: Yes. Hi, hello. Thanks for bringing that issue up. Yes, so we put together a panel of experts that adjudicated every case that we enrolled. So we made sure that we had several different criteria and that these patients met each one of them. So we are very confident that these patients really had ME/CFS and it was a post-infectious ME/CFS. So we screened hundreds of patients to enroll and the right patient population. So I'm pretty confident we have the right patient population. Thank you.
Barbara McMakin: I have another question in the Q and A box. This one will be for Dr. Whittemore. It's about the research roadmap. In the past, patient representative feedback to HHS has not been substantially incorporated. How do you plan to ensure that patient input from this working group will have tangible impact on the direction of your work and not be solely symbolic?
Dr. Vicky Whittemore: Yeah, thank you for that question. It's really the reason why we have involved so many individuals with lived experience both on the working group of council as well as in helping us to plan the webinars and to actively participate in the discussion and formation of the research priorities.
So in a previous experience I had working at a nonprofit where the hallmark symptom of the children with that disease are seizures, we were heading down a path of planning a lot of research on epilepsy and seizures in that genetic disorder when the input we got from parents and individuals with the disease was really that it was the cognitive and behavioral issues that were more important to them. And it really shifted the way we thought about moving things forward.
So it’s really that kind of critical input in hearing from the community about what is most important and critical to you that will help to shape things going forward. So it is not at all going to be symbolic and we are here and will provide many different opportunities for input and feedback from the community. So thank you.
Barbara McMakin: Great, thank you. We are almost at time, but we have time for one more question. Yuval Shefi, do you want to unmute and ask your question please?
Yuval Shefi: Hey, do you hear me?
Barbara McMakin: Yes.
Yuval Shefi: So I wanted to ask if the weakness of the muscles that we are also dealing with is part of the PEM research or if it's another thing to investigate?
Barbara McMakin: Dr. Nath, do you want to take that one?
Dr. Avindra Nath: I'm not sure I really understood the question. So it's not really weakness per say in the muscle. It's more of exhaustion after exercise, exercise intolerance that these patients deal with. Weakness is a very different aspect. That means that there's either muscle pathology or the nerves themselves are damaged. So example, you have a stroke or something, you could get weakness. So I don't think that ME/CFS is really a disease of muscle weakness.
Dr. Vicky Whittemore: Dr. Nath, do you see muscle weakness after deconditioning? So say for someone that's bedbound for a long time?
Dr. Avindra Nath: Yeah, that's not what at least in neurological terms I would call weakness. That is just fatigue and exhaustion and exercise intolerance, which is very different.
Barbara McMakin: Great. Thank you. It looks like we're right at time. Thank you again, Dr. Roy and Dr. Gottschalk for joining us to talk about your research today. A recording and transcript of the webinar will be posted to the NIH ME/CFS website soon.
In closing today's telebriefing I'd like to remind you about our listserv for updates from NIH. To be added to the listserv, please visit the NIH ME/CFS website, which is www.nih.gov/mecfs and click on join our listserv. Thanks everyone for joining us today and for the thoughtful discussions. Have a great afternoon. Thank you.
This page last reviewed on June 7, 2023