CURE-3

C

Barts-MS rose-tinted-odometer: ★★★★★ (still seeing red, despite Summer having finally arrived)

I am considering retraining as a medical philosopher. The thinking of the MS research community is riddled with fundamental errors that could be sorted out by applying basic philosophical principles. One example is the diagnostic tautology we are wedded to in how we define MS as a disease. Another relates to the classification of categorical MS disease states. Defining an MS cure, etc. I am also being criticised for supporting two conflicting, juxtaposed theories about the potential cause of MS. How can I ‘believe’ MS is caused by EBV and at the same time talk about IRTs (immune reconstitution therapies) potentially curing MS as an autoimmune disease.

The reality is that scientists are not religious and don’t hold beliefs. Scientists put forward hypotheses, which are then tested and refined. Over time hypotheses get rejected and/or evolve and if the experimental evidence becomes overwhelming they enter the canon of human knowledge as facts. In comparison, beliefs are immutable and cannot be challenged. Therefore, I don’t believe EBV is the cause of MS and I don’t believe MS is an autoimmune disease. I hypothesise that EBV is the cause of MS, I hypothesise that MS is an autoimmune disease and I hypothesise that these two theories are not mutually exclusive, i.e. MS can be caused by EBV and still be an autoimmune disease. In other words, EBV is the driver of autoimmunity and by removing EBV from the MS causal pathway you prevent or cure MS. 

To prevent EBV infection we are exploring doing an EBV vaccine trial in people at high risk of MS and then following them to see if they go on to develop MS or not. This experimental paradigm is well-rehearsed and relatively easy to understand. 

What is not easy to understand is how EBV causes MS. One theory is that EBV simply provides autoreactive B-cells and T-cells with a survival advantage and as a result, they persist, expand in numbers and become dysregulated, which tips over into autoimmunity that becomes self-perpetuating. How EBV does this is not known. One mechanism that I have proposed is that because EBV infection causes B-cells and T-cells to hyperproliferative, i.e. go through many cell divisions, they acquire so-called somatic mutations in their genomes that sets the stage for autoimmunity.

There is mounting evidence in MS that the majority of pwMS have somatic (in the body and not in the germline) mutations in T-cells and B-cells (see studies below). These mutations could provide these cells or clones with a survival advantage, based on simple Darwinian selection principles, which explains why they persist and expand in number. Think of these cells as being like a kind of benign tumour. The important thing is that these cells can be killed using aggressive immunodepletion strategies such as AHSCT or alemtuzumab treatment. 

Another thing to remember is that it may not be one but several somatic mutations that are required to trigger autoimmunity. So if you purge the downstream autoimmune clones, but leave the upstream driver clones behind, they may have the potential to acquire new mutations and hence reactivate autoimmunity in the future. This could explain why some people who go into long-term remission after HSCT or alemtuzumab treatment breakthrough many years later with recurrent MS disease activity. 

The two studies below show that pwMS harbour many somatic mutations in their circulating B-cells and T-cells. These data not only underpin the hypotheses presented above, but also support the hypotheses that MS is an autoimmune disease triggered by EBV and that it can be cured by an immune reconstitution therapy. 

So I won’t be deterred by my campaign to define what an MS cure looks like so that we can look for it and claim it as a victory in the management of this awful disease

Yes, I am a big supporter of the hypothesis that MS is a curable disease and this position is absolutely compatible with my positions on the role of EBV and autoimmunity in causing MS. Do you disagree?

The great tragedy is that if IRTs cure MS in a proportion of pwMS, why are we not using IRTs more widely? Now that is the big story that can be told another day.  

Our current approach to treating MS. Photo by Luis Villasmil on Unsplash

van Horebeek et al.  A robust pipeline with high replication rate for detection of somatic variants in the adaptive immune system as a source of common genetic variation in autoimmune disease. Hum Mol Genet. 2019 Apr 15;28(8):1369-1380.

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.

Valori et al. A novel class of somatic mutations in blood detected preferentially in CD8+ cells. Clin Immunol. 2017 Feb;175:75-81.

Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune-related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8+ cells (85% of mutations). In follow-up after a median time of 2.3years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPA1 and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

46 comments

  • When you mentioned that you think a cure is quote ‘Less.” than 5-7 years away in a previous comment what did you mean by that ? How are we going to cure ms in “Less.” than 5-7 years ?

    • Does it really matter what Prof G thinks when a cure will come? He can be right or wrong, he said it could come as early as 5-7 years, even if he makes a promise, he can still be right or wrong. Given all the work’s been done and how much faster biology advances compared to before, I have faith the disease can be halted 100% in 5-7 years :).

      Just do your exercises and live well every day, and the day will come.

      • I think what prof G and a lot of others are saying there is a cure now for some if you define a cure as stopping progression.

        Some highly effective DMTs that are available now and in some but not all may halt MS and normalise brain atrophy

        But these treatments arnt getting used front line. People have to wait for further damage to revive them.

        No doubt there will be better treatments in 5/7 years time, if they are proven to work. But for some how much damage can be done in that 5/7 years. Even if a ‘cure’ comes

        Not many diseases have a cure

        But your right live to the best and healthiest you can, dont really on pharma to come up with something new.

        • “I think what prof G and a lot of others are saying there is a cure now for some if you define a cure as stopping progression.” 🙂 I think Prof G likes to exaggerate to make a point. In my opinion, what he is doing is in good heart and most part of me appreciate him. However I sincerely doubt if this type of behaviour is entirely ethical.

          • What is unethical about discussing a cure for MS? It is not like he is advertising his private practice or specific MS treatment. Both AHSCT and alemtuzumab are hardly used to treat MS. I think that is the point he is trying to make. If you can show some people who receive these treatments are cured other people may want
            to choose these treatments for themselves.

          • I’m not expert but their are people in over decade/s long remission with no clinical worsening because they used lemtrada or HSCT, these are the facts not just options.

            Is this a cure or not?

            Hopefully soon enough there are highly effective treatments for all with MS that have very little side effects.

  • Prof G,

    “I am considering retraining as a medical philosopher.” Stop having these hissy fits and get back in your pram. You are needed to sort out MS. I suspect we are not that far away. A nice weekend away in Norfolk by the coast (no wine) should do you the world of good or Lymington as you’re south of the river.

    What’s needed is a shake up of the Boards of the various MS organisations. To conquer MS we need young, curious, risk taking, tech savvy researchers and neuros / MSologists. Too many academic / neuro experts don’t seem to understand the word ‘retirement’. I see that you are on the Board of the European Charcot Foundation (average age 83). You are the youth representative and are only a few years from a bus pass! I went to a technology conference a few years ago and a boss at a major company admitted off the record that they wouldn’t consider employing anyone under 35. A bit extreme for MS research / MSologists, but there is certainly a need to revamp these boards to ensure fresh ideas and a desire to skate things up and challenge the establishment view.

    https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwj-pp78vOnwAhWLsRQKHWEyCD0QjBAwAnoECBQQAQ&url=https%3A%2F%2Fwww.charcot-ms.org%2Fabout&usg=AOvVaw0SBYNFSk4Z64KaZfRu3Y9m

  • This is interesting.
    Am I right in thinking that somatic mutations might be repairable using gene therapies? Though it would require being able to

    (a) identify the somatic mutations
    (b) have a mechanism by which to repair them reliably and permanently
    (c) prove that this mechanism is safe

    and it still wouldn’t fix any existing damage but it would be a start…

    This of course in addition to EBV vaccines to stop the damage occurring in the first place…

    • Re; “somatic mutations might be repairable using gene therapies”

      Yes, they can theoretically be repaired by gene therapy. But we have no idea which mutations are the autoimmune driver mutations at present. We can hypothesise, however, based on their role in B and T-cell biology.

  • I believe You do more critical thinking about Multiple Sclerosis than Most Neurologists.
    I believe many scientists are also believers, in something. Even Atheists have beliefs.
    I believe My Really bad case of EBV in college started me on the MS path.
    I believe Glatopa works for me. At 63, my immune system is already winding down.
    I believe I have Never Really seen Multiple Sclerosis explained Definitively.
    I believe EBV vaccine is a good study. Cure is possible. Eradication Divine.
    Can I sneak in an example of present practice that needs to change?
    Stop using gadolinium. Take the checkbox off the form.
    Be a Philosopher And Doctor. You do both well😎👍🏼

  • Received an email from the MS Society this morning about the Octopus mega trial for people with progressive MS, aiming to recruit later this year; just wondering your thoughts on this and the treatments going to be trialled. Thank you.

  • I have slow, slow PPMS. (And probablya lot of genetic risk genes due to a heavy dose of Norse ancestry.) I am not interested in therapies which batter my – otherwise very useful – immune system. I am interested in clobbering EBV. Are there any trials looking at potential benefits of EBV treatment in people with “advanced” MS?

    • There is no known way, currently, of effectively inhibiting EBV in humans. A lot of oncologists are interested in this question too because of various EBV-related cancers and they don’t have a therapy either, except for the same kinds of immune-depleting therapies used in MS. Cladribine is a highly effective EBV treatment and the CHARIOT trial is looking at subcutaneous Cladribine for advanced MS. Perhaps look for a neuro who is willing to prescribe you that? Alternatively, find a sympathetic GP who is willing to let you trial Combivir. Personally I would be far more worried about preventing as much brain damage as possible than about side effects from clobbering the immune system.

  • Somatic mutations are non genetic influence on gene expression(my definition) 🙂

    Example : If you work in an nuclear plant and you develop cancer thats most certain cause by exposure to radiation that cause somatic mutations in your cells
    If you smoke, if you get to much sun,,.. etc

    Basically all the mutations we get in to our life time

    Question:

    Does Ebv cause this somatic mutations in t and b cells ?

    If you are 3 or 4 years old and you gets ms does that makes for enough time to get somatic mutations in your very young immune system? How does that hyphotesis fit?

    Eyestarday Doc Mouse put this post

    HLA-DRB1*15:01 is a coreceptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur J Immunol 2021.

    Sure enough is not only somatic mutations what you inherit its also important

    With such an ubiquitous around the world should be more people and their somatic mutations making more ms patients

    Nice post

    Sorry for so much questions

  • Re the EBV vaccine, don’t just target children at risk of MS. There’s Burkitt’s Lymphoma, CFS, bad glandular fever etc. There are so many malignant and ‘auto-immune” conditions linked to EBV, it’s amazing that a company like Sanofi Pasteur, MSD, AZ, Pfizer or GSK hasn’t realised the enormous potential profit in it for them and developed a vaccine. The new RNA vaccines for CoVID-19 could be the test bed for the breakthrough technology.

        • “I’ll order a dose tomorrow.”
          Why it won’t help you’re already infected.

          They have new vaccines for CMV..EBV..and Zika

          Vaccines against infections transmitted from mother to baby
          Cytomegalovirus (CMV) vaccine (mRNA-1647)
          Zika vaccine (mRNA-1893)
          Vaccines against common viral infections with high unmet need Epstein-Barr virus (EBV) vaccine (mRNA-1189)

          https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-progress-prophylactic-vaccines-modality-cmv

          • It could help Anon. One way, thousands of researchers are looking into in terms of curing HIV is by making a vaccine for which the individual will make broadly neutralizing antibodies against HIV so antiretroviral drugs would no longer be needed for those already infected. Essentially, it would teach their bodies how to make their own medicine against HIV. Now concerning EBV it is much easier to make a vaccine against EBV than HIV therefore their is a possibility that this could benefit people already infected with EBV that have multiple sclerosis. To say a vaccine would have 0 % effect on those infected is unlikely. Just as before going on Ocrevus you need to get revaccinated against the Varicella zoster virus ( chickenpox ) even you are already infected with it because the vaccine works.

          • This is only a ‘development candidate’ going through phase 1 trials, so getting this treatment isn’t possible currently. It isn’t CoVID, so it’ll be another decade before we can order one. Also, as it’s an mRNA vaccine so you’ll probably need to store it in a minus 70C freezer.

          • Zostavax is effective against Shingles in those who are, by definition, already infected with varicella zoster. They are herpesviridae of the human variants 3 and 4. Why would vaccination help with HHV3, but not HHV4?

  • Not only causal, but a very smart general practitioner sent me for extensive testing as I was “progressing” and it was determined that I had an ACTIVE current EBV infection (as well as historical infection). I had zero symptoms of illness, just a slow decline over a year that was termed MS progression.

    Put on an antiviral (no there are no excellent antivirals, but it was enough), my MOBILITY turned around. I will be first in line for an EBV vaccine once it arrives.

    Managing “all the things” is part of the “cure”. Prevention in the future being number 1.

    EBV is hosted in B memory cells. This is why I was happy to do an IRT. Clears out a good deal of B memory cells, producing naive cells. The experiment continues. This is why I find the cut off for DMTs in mid 50’s or with certain EDSS levels ridiculous.

    • “I will be first in line for an EBV vaccine once it arrives.”

      Not sure it will help..as you already have EBV.

      • Before getting on Ocrevus you need to be revaccinated against the Varicella zoster virus even though you are already infected with it. The reason why they give you the vaccine even though you already have it is to protect you from the effects of that virus by increasing your immunity. In essence a vaccine against EBV will also have an effect for those who are already infected. A way people try to cure HIV is by developing a vaccine for which broadly neutralizing antibodies are made and therefore the individual can control the HIV virus with their own immune system.

    • “This is why I was happy to do an IRT. Clears out a good deal of B memory cells, producing naive cells.”

      What IRT did you get..?

    • What’s this smart GP’s strategy managing MS on antiviral moving forward? Is it safe to take antiviral long-term? How long have you been on antiviral and are you tolerating it well? Sorry to bombard you with all these questions!

  • “So if you purge the downstream autoimmune clones, but leave the upstream driver clones behind, they may have the potential to acquire new mutations and hence reactivate autoimmunity in the future. This could explain why some people who go into long-term remission after HSCT or alemtuzumab treatment breakthrough many years later with recurrent MS disease activity.”

    This is why you’re way off with cure talk…cure is for all..now is only cure for some.

    “I’ll get right to the point. Gains from my 2010 stem cell transplant to halt my aggressive multiple sclerosis are slipping………The transplant saved my life–I was, and still am, beyond fortunate. For four years it helped me feel almost normal again. And I purposefully took every advantage, living life with my right foot firmly on the accelerator, figuratively and literally. It allowed me to drive again, travel the world again, and even snowboard again. But I knew that I might have to write this post one day.

    As evidenced by the just released 3-year update of HALT-MS in JAMA Neurology, the success rate of the trial has been unprecedented in MS, with nearly 80% of patients showing no evidence of disease activity after three years, and with some patients seeing a marked reversal in disability, myself included (2.5 EDSS points!). Unfortunately, it appears that with time the treatment’s durability is tested, as early numbers suggest fewer than 70% exhibit zero disease activity (relapse, new lesions or EDSS increase) at year four, a figure that drops below 60% at year five. Still powerful results, but far from across-the-board remission.”

    https://forums.activemsers.org/forum/activemsers-org-forums/dave-s-sct-journey/1826-gains-from-my-transplant-are-slipping-begrudgingly-weighing-plan-f

    • >https://forums.activemsers.org/forum/activemsers-org-forums/dave-s-sct-journey/1826-gains-from-my-transplant-are-slipping-begrudgingly-weighing-plan-f

      Note that he had highly active, disabling MS for at least four years before getting HSCT, and it still gave him five years basically disease free with significant disability reversal, which is nothing to sneeze at… For people with milder MS who get an IRT immediately after diagnosis the prospects are probably even better.

      • “gave him five years basically disease free with significant disability reversal, which is nothing to sneeze at…..”

        No…it was awesome result for 5 years but then it came back and he later has
        had to use wheelchair.

        This was the analysis of that same HALT MS trial:

        “None of the immune cell reconstitution or expression patterns at any time‐point post‐HSCT correlated with the 5‐year clinical outcome. However, prior to HSCT treatment, the group of 16 patients who remained healthy throughout the 5‐year study had significantly higher numbers of central memory CD4 and CD8 T cells in peripheral blood than the seven participants who experienced an MS‐related event…”

        So 7 out of 23 failed at the 5 year mark………hsct is far better than any drug…..but still so far from a cure. Yes some of first treated in u.s. in
        2000 are still in 20 year remission. Australia has some at 10 years including
        one that was ppms.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543487/

        “For people with milder MS who get an IRT immediately after diagnosis the prospects are probably even better.”

        No..it doesn’t seem to work like that at all.

        In Sweden they have done many hsct as first line after diagnosis….and
        the woman said they just told her…”We know 30% fail treatment but
        we don’t know why.”

        • > ”We know 30% fail treatment but
          we don’t know why.”
          So in other words if you use HSCT first line it’s a cure for 70% of people? That’s an amazing result. If you had a drug that wiped out cancer in 70% of patients no-one would have a problem calling that a cure.

          • “If you had a drug that wiped out cancer in 70% of patients no-one would have a problem calling that a cure.”

            No…don’t think Oncologists would call that a cure. Not when 30% of patients expire from their condition.

            Bigger question is why Neurologists continue to treat with drugs that don’t stop progression
            instead of hsct. Answer….they are neurologists and not hematologists.

      • “Note that he had highly active, disabling MS for at least four years”

        He only had ms for four years so he still alot of brain reserve to
        allow for improvement.

  • So we are missing some info here. What do you take to treat the mutation of these cells infected by the EBV? What do you take after receiving aHSCT (as I have) and failed after 1.5yrs transplant? I had EBV in 1996 at age 18. Worst case my doctor said he ever saw. I got diagnosed with MS in June 2002. Have tried 6 dmds and failed. aHSCT in May 2018 with an EDSS 5.5 and failed come August 1019. EDSS is now a 6.5. I am actually going on Ocravus in July 2021 to see if I can stop the progression of my disability. What do you take if this is the case?

  • This constant thrashing about the agonizingly precise definition of an MS “cure” so we can “claim victory” tells me that what is being proposed is too narrow to be a cure. The battle over the use of cure is about leveraging the happy connotations that flash through the mind unbidden upon hearing the word. To us plebs it means “Yaaah HOO!! MS is never coming back!! Not in 3 years, or 5, or 15 or EVER!!!”. A cure is more akin to what Jesus did for the lepers. There were no time limits, no “you only get cured for 15 years tops and only if you have early leprosy or a young immune system or you’re strong enough and determined enough to endure the treatment”, you’re just….cured, period. What all this arguing over “cure” amounts to, is what verbiage can be use in advertising to patients, bean counters, and the bodies that say who can have what med. It gives everyone a warm fuzzy up front before they have to actually read the fine print. And if the only people you can cure are the happy-path patients who are young and strong, then those of us who are reasonably past that are not quite as impressed by the label. I’m in no way trying to downplay the sometimes spectacular results of the treatments and meds in question – getting a few years of no activity and no progression would be fabulous at whatever age. But it does have a Flowers for Algernon vibe if you’re likely to have to watch it all melt away at some point.

    And I’d just like to mention, a lot of people keep comparing MS to cancer. I’ve had cancer twice – two different kinds – and I don’t recall anyone using the word “cure”. They did some talking of 5 year survival rates, but not really anything using the word cure. I think cancer docs have historically gotten their posterior portions and egos handed to them enough times by claiming too much too soon, or harming their patients from ever-more-extreme treatments that it’s made them wary of the c-word. And rightly so. MS docs might want to take note of those lessons.

  • I was diagnosed with relapsing remitting multiple sclerosis and 12 of 2012 and now I am only 48 and struggle to move! Luckily I still can with the use of a walker!!! A wheelchair when I leave the house

  • Yes, I disagree.
    Sorry to say Doctor Mouse that, the only fact you’ll have achieved, it will be the retirement. Until then… not much in MS research.
    All your certainties and cures are based on your belief (“I want to believe”), which is not science, but just a brick out of the blue. And based on your brick, you’ve been entitled (used? abused?) to jump on it to bully competitors (other bricks). Wasn’t it enough to focus on your autoimmune Goddess instead of “bulling” around?
    Also MS associations, members of your friends at MSIF (you state the false when you say MSIF represents “all of the MS Charities from across the world”. Again, “bulling” is your science?), had to admit that there’s no proof of autoimmunity, only beliefs (don’t worry, they still serve drug therapies). Enjoy food and wine and sorry for my Oxford accent 😉
    All the best,
    Mickey Mouse
    PS: “Most MS experts believe it to be an autoimmune disease, although no specific antigens (proteins that stimulate the immune system) have been identified in MS. ” https://www.nationalmssociety.org/What-is-MS/Definition-of-MS/Immune-mediated-disease

    • I find your post to be very strange. Science evolves as knew hypothesis are tested. I don’t know why this is considered bullying. The belief that MS is an autoimmune disease is also not established and not all neurologists believe it to be true. To move science and treatments forward, new hypotheses need to be tested.

      Ever asked yourself what if MS isn’t an autoimmune disease? Then ask yourself what are the long term implications for science and treatments of this is the case. Follow that logic to its conclusion and see where you land.

      • Some of us reached that conclusion years ago but importantly there obviously is an important immune system component. That revelation has, shall we say, failed to achieve traction.

          • “If at first, you don’t succeed, try, try again, then give up. There’s no use being a damn fool about it”.-MD2

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