Black Swan?

B

Is this the black swan I have been looking for?

We need to be able to explain smouldering MS and why pwMS get worse despite having no evident disease activity (NEDA) on DMTs. One of the hypotheses is that something is occurring within the brains and spinal cords of pwMS. I have referred to this in the past as the field hypothesis and have suggested that it could be due to an active virus within the brains of pwMS. I have always made the point that the two viruses with most of the evidence behind them are EBV and HERVs, particularly HERV-W.

This study below strongly suggests that the HERV-W envelope protein may be driving smouldering MS. It would be interesting if the ENV protein is found in SELs (slowly expanding lesions). This study supports our Charcot Project and the urgent need to formally test HAART (highly active antiretroviral therapies) in MS. Our INSPIRE trial, which was negative, was not HAART as it only tested one anti-retroviral and integrase inhibitor.

Do you have the appetite for another push at getting funding for an add-on HAART trial in MS? The case for doing it is compelling both from an epidemiological and basic science perspective.

LET’S DO IT!

Kremer et al. pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Jun 18

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

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.

53 comments

  • Do you have the appetite for another push at getting funding for an add-on HAART trial in MS?

    Not really. I remember attending the research days and getting very hopeful with the work of Prof Gold. The trial took ages and was another dud. A HAART trial will take ages to fund, ages to plan, ages to get through ethics committees etc. etc. You are looking at a good ten years before Phase 3 reports and a few more years to get a licence (if trials are successful). So bored of the slowness of MS research. Lazy researchers and greedy pharma focused on relapses (low hanging fruit) not the mechanisms that are destroying MS brains. MS sufferers have been let down, while pharma make big profits and neuros and researchers get paid regardless. Do something innovative by getting this trial done quickly (MSers to get HAART treatment -Phase 1 trial – in 2020 and I’ll eat my hat. The lack of urgency is scandalous.

    • Well said.
      The slowness of MS research is indeed boring, sometimes it feels to me that it doesn’t do much more than keep people in jobs.

      MS might be their livelihood, but MS is our LIVES.

      I agree, the lack of urgency is scandalous.
      No real incentive to look for a cure either is there when the pharma companies pick up four grand a month per patient off the NHS.
      30 years ago AIDS was a life sentence, it isn’t now as long as you take the medication….how come that hasn’t happened with MS??

      The medical community need a rocket up their a*s

      • I often think about AIDS and how real effort and commitment delivered a cure. AIDS is caused by a virus (HIV) – it looks as if MS is also caused by a virus. Why not replicate the structures and teams which conquered AIDS for MS? For too long neuros have tried their hand at virology which isn’t there specialism. We need the best virologists (those that worked on AIDS) to work on MS and develop treatments to address the virus/es not the inflammation which is a consequence of the virus.

          • What on earth is sexy or cool about AIDS? I doubt that all the people who have suffered massive stigma living with the disease and the fear of passing it on would say so.

    • Agree with you Bob. I’m pretty fatigued out with the cycle of promises / hope from MS researchers. After 20 years I’m still waiting for the remyelination therapies (I raised my bit for the MS society c. 10 years ago), the neuro-restorative therapies and the neuro-protective therapies. The researchers try hard, but as we near 2020 I’m not confident the field has moved on much from the anti-inflammatories. I got over-excited by the B cell treatments, but Hauser’s observation that many patients still go progressive killed off my hope. Prof G and co need to see this from a patient’s perspective – we don’t have time on our side. Promises of treatments in 10-15 years time don’t feel me with excitement.

    • Julian Gold and I put in three grants to get a HAART study funded; all were rejected. The MS community (peer reviewers) simply don’t like the hypothesis.

      We then shopped the hypothesis around to three Pharma companies that make antiretrovirals. Merck (USA) bought into the hypothesis and funded the raltegravir study. Gilead said they would supply drug (HAART) if we could get the trial funded from another source, which we couldn’t. This is a CATCH-22. GSK/Viiv have said no.

      We probably need somewhere close to £4M to do a proper proof of concept phase 2 HAART trial in MS. If you can help and find us a funder we will do the trial.

      The delay in getting this off the ground is not for lack of trying. Sometimes science is just slow because the ‘wider MS community’ is simply not ready for alternative hypotheses.

      • Try a “go fund me” to get your resources for the trial.

        RE :“The wider MScommunity is simply not ready for the alternative hypothesis.”

        What is the accepted hypothesis? No one knows the causes of MS.

        • In the UK research that is funded via ‘unconventional’ routes is often frowned upon. Not so in the US and other countries.

          UK academics think the peer-review process is essential for making sure quality research is done. At the same time, the peer review process often prevents unconventional ideas/hypotheses being tested.

      • J K Rowling (mum had MS) is worth over £1 billion, Sharon Osbourne (son has MS) is worth tens of millions, Michelle Obama (?father had MS) is worth many millions. The AIDS research success was because big names (eg Elton John) fronted the project and wrote out cheques. We need the equivalent in MS. The other issue with AIDS is that there was no dogma or academic reputations at stake. Too many old timer MSologists are stuck in the 70s – showing that MS is caused by a virus and can be effectively treated would undermine their careers and reputations. The MS research establishment is the real reason why progress has been so slow and new approaches stymied. Producing lots of research papers is a poor metric for showing progress in under and treating MS / benefitting patients. EAE is also a chief reason for the lack of progress ie given that the cause of MS is likely to be viral.

        • I have tried to contact JK Rowling many times; via email, written letter to her agent, publisher and home address, via Twitter and her website, but have never had any response. Again is not for lack of trying. 🙁

      • Is this “wider MS community” made up of doctors/scientists/health workers or people who actually live day to day with the knowledge they have effectively been handed a life sentence?

        Now the internet is here us mere mortals can go back and look at stuff people were talking about/publishing/saying was a near breakthrough 20 years ago and making our own opinions that if the “experts” don’t even know what causes MS, then how the heck can they even be looking for a real cure?
        We do NOT have the luxury of time.
        It’s scandalous!

        • I’ve been looking at the Anne Rowling (mum of JK) clinic site in Edinburgh. They are/were doing trials on microbiome stuff. I’d never heard of it (though I do try and keep to the OMS stuff way of eating as best I can).
          If this microbiome stuff is basically you are what you eat, why don’t neurologists give people guidance on what they should and shouldn’t be eating? The blanket “you must eat healthily” spiel they come out with is as much use as a chocolate fireguard innit?
          Even if this microbiome stuff turns out to be nothing, patients knowing what to eat/avoid is cost free to the NHS and would give patients some control so that they could feel that they can be doing something to help themselves.

          Proper eating healthy won’t kill us MS’ers off,.. no toxic side effects etc etc…so why isn’t this a no-brainer (god what a pun for a PWMS!) and told to to every patient?

          Not a cure, but if there is the possibility it would help it should be told to us all BEFORE the years and years of trials take place.

  • Are these researchers connected with GeNeuro, the company that is developing the HERV W envelope protein targeted monoclonal antibody? If so, what is your take on their drug?

    • The GeNeuro phase II MS data looks pretty good (a nice reduction in atrophy with a very good safety profile). Robert Glanzman and the wider clinical team at GeNeuro are managing their program very well indeed. It’s early days but could be the add on product people have been looking for. That’s my opinion of course and a neurologist I ain’t.

    • Hi Marc,

      I think you’re spot on! Herve Perron, one the authors of this paper, happens also to be scientific director for GeNeuro.

      My French isn’t great but you can apparently find an interview from 2018 where he’s describing these results to some baffled reporter from a local TV station..
      https://youtu.be/ZHA7CtvEe6g

  • This is very interesting and definitely worth further research! I no longer feel excited when my MRI shows NEDA because I know it’s still smouldering away in my grey matter!

    • ” I no longer feel excited when my MRI shows NEDA because I know it’s still smouldering away in my grey matter!”

      Exactly why people ditching DMTs and getting hsct.

  • There is no greater need in the field of MS research than to find the root cause of the disease. To enable prevention, treatment before the hideously complex disease processes get underway. And hopefully to pull a true brake on established disease. Rather than fire fighting, which is the most current treatments do (mostly whilst destroying the immune system).

    Please push hard for this!

  • This is the research that we MSers must find a way of funding. How about a crowdfunding project to kickstart the project? In the meantime PrEP is fairly easy to get hold of, if I approach ch my GP and claim I am activly engaging in high risk behaviour. (I am HIV negative so should be eligible. ) Would PrEP be any good as an antiretroviral? Iheory I could get hold of it quickly, but would it work? Someone please advise.

    • ‘How about a crowdfunding project to kickstart the project?’

      Surely lots of people would support such a project if it was started up? Lots of people raise money for MS charities. This would a very tangible thing (hopefully) to raise funds for that would galvanise a lot of support.

    • Both are cytidine analogues which inhibit viral reverse transcriptase activity. Raltegravir which was tested and failed was an integrase inhibitor. Articles suggest that current HIV protease inhibitors, including ritonavir, indinavir, and saquinavir, have no efficacy against HERV-K10 protease.

      However, the HAART therapy could see efficacy through the nucleoside analogs

    • PrEP is a safe combination but probably not enough to control MS-HERV. A 3 drug combination including NRTI Lamivudine (emtricitabine is its equal on the PrEP combination but with no data on controlling HERV in contrast to Lamivudine), with NNRTIs Nevirapine or Efavirenz is a good combination with some accumulated data (in vitro and case studies) for the MS case.

  • Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects

    Time and time again “The colective cyborg” have said that all antibodies are pathogenic that we must get rid of them

    Here they said otherwise

    🙂

  • Black snaw is in the air 🙂

    https://www.neurologyadvisor.com/topics/movement-disorders/parkinson-disease-incidence-lower-in-hep-c-patients-recieving-antivirals/?utm_source=newsletter&utm_medium=email&utm_campaign=na-update-20190613&cpn=&hmSubId=&hmEmail=VHU0u6r2Q_Y1&NID=&email_hash=88dcf3bd84ab18b95096dd9b5aa1a8cd&mpweb=1323-56560-10917

    Parkinson Disease Incidence Lower in Patients With Hepatitis C Receiving Antivirals

    The results seem to support the theory that HCV infection is a risk factor for developing PD. Antiviral therapy has shown potential in lowering this risk,” the authors write.

    Can we cacth him?

  • But Glanzman is skeptical, as he posits another reason for Gold’s disappointing MS trial—the use of an antiretroviral drug to target what Glanzman thinks is an inactive virus. If the HERVs that have been linked to these diseases are incapable of replicating, “trying to approach them with an antiviral treatment is not going to be effective,” says Glanzman. Instead, he and his GeNeuro colleagues are developing an envelope-targeting antibody called GnbAC1 that binds to a surface subunit of the envelope protein to block its interactions with toll-like receptor 4 carried by microglia and macrophage cells and has been recently shown to promote myelination in rat nerve cell cultures. Last March, the company concluded a Phase 2b trial with 270 MS patients in Europe that showed preliminary evidence of the drug’s effectiveness in treating the disease. In results that were presented at a conference on MS research in Berlin last fall, patients who got the antibody at the highest dose experienced 31 percent less shrinkage of cortical tissue, a hallmark of MS, compared with patients treated with placebo for six months. Treated patients also experienced a 63 percent reduction in the formation of “T1 black holes,” the brain lesions associated with the most severe damage to the central nervous system.

    https://www.the-scientist.com/features/can-viruses-in-the-genome-cause-disease–65212?fbclid=IwAR3Q9gDLwEWHDrIAFssGiEfuCSJkNcPqmqgKNyD6go9XBcqYTxlSI82mvQs#reference12

  • two further plausible contributions of EBV involvement into MS. If
    EBV is truly a pre-requisite and/ or the main contributor of MS pathogenesis,
    then the fact that most of the world’s population are infected
    by EBV yet only a small proportion go on to develop MS (or other
    EBV related diseases), needs to be addressed. Genetic risks for MS, such
    as the presence of the HLA allele DRB15*01 and absence of A*02, have
    been shown to be increased in combination with EBV infection
    (Sundqvist et al., 2012), but this still does not account for 100% of MS
    cases. It would be interesting to know if individuals with the major
    genetic risk factors for MS, in the absence of EBV infection, developed
    MS.

    EBV and MS: Major cause, minor contribution or red-herring?

    Multiple Sclerosis and Related Disorders 16 (2017) 24–30

  • Although relapses were reported by some of our subjects, the comparison of disease activity and
    EBV copy number was not a primary goal in any of the three studies described here. The logical

    follow-up to this study is to test whether EBV shedding is related to disease activity across an entire
    cohort, for example, by comparing salivary EBV levels with MRI activity. If salivary EBV levels are
    found to be linked to MS disease activity, it would then be important to test whether EBV antiviral
    drugs can be used to treat or even prevent the disease.

    Why dont you do this ?

    Seems really straightforward

    😉

    EPSTEIN BARR VIRUS SHEDDING IN MULTIPLE SCLEROSIS:
    SIMILAR FREQUENCIES OF EBV IN SALIVA ACROSS SEPARATE
    PATIENT COHORTS

    10.1016/j.msard.2018.07.041

    • I had glandular fever at about 23 and again at about 25.
      I also had shingles at age 9

      I keep seeing these 2 again and again in articles about MS.

      Why does it not occur to the Neurologists to ask these simple questions when people are being diagnosed? Is there not a database where common former ailments of PWMS could be collated?
      I am astounded they don’t take a DETAILED medical record of each person diagnosed and see what the common ailments have been…how are they ever gonna find a cure when they can’t agree what causes it??
      Could someone in the medical community not set one up?

  • Still airborn

    Schizophrenia is Associated With an Aberrant Immune Response to
    Epstein–Barr Virus

    human herpesvirus capable of infecting the central nervous
    system and establishing persistent infection. Methods: We
    employed solid phase immunoassay techniques to measure
    immunoglobulin G (IgG) class antibodies to EBV virions and
    defined proteins in 432 individuals with schizophrenia and
    311 individuals without a history of a psychiatric disorder.
    Western blot testing was performed to document reactivity
    to specific EBV proteins. Polygenic risk for schizophrenia
    was calculated from genome sequencing arrays. Levels of
    antibodies between the groups were compared by multivariate
    analyses incorporating clinical, genetic, and demographic
    measures. Results: Individuals with schizophrenia
    had marked elevations in the levels of antibodies to EBV virions
    as compared to the control population. Further analyses
    indicated increased levels of reactivity to EBV-viral capsid
    antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-
    1) or to other human herpesviruses. Western blot analysis
    confirmed increased reactivity to VCA proteins in the group
    of individuals with schizophrenia and documented a lack of
    increased levels of antibodies to EBNA-1. Genetic analyses
    indicated an additive effect of increased levels of antibodies
    to EBV virions and genetic susceptibility to schizophrenia,
    with individuals with elevated levels of both type of markers
    having a greater than 8.5-fold odds of a schizophrenia
    diagnosis. Conclusions: Individuals with schizophrenia have
    increased levels of antibodies to some but not all EBV proteins
    indicating an aberrant response to EBV infection. This
    aberrant response may contribute to the immunopathology
    of schizophrenia and related disorders.

    The finding of increased levels
    of VCA but not EBNA-1 antibodies in individuals with
    schizophrenia is thus reflective of an aberrant immune
    response to EBV infection. Aberrant responses to EBV
    have been described in a range of EBV-associated disorders
    including autoimmune diseases such as multiple
    sclerosis29 and systemic lupus as well as neoplastic conditions
    such as nasopharyngeal carcinoma.30
    Increased levels of antibodies to EBV virion and VCA
    proteins were not associated with cognitive functioning
    or symptom scores but were associated with an increased
    prevalence of the deficit syndrome. EBV virion antibodies
    were also significantly increased in individuals who were
    receiving the mood-stabilizing medication valproate. This
    finding, which should be verified in larger samples, is of
    interest in light of the immunomodulatory effects of this
    medication which are likely related to its effects on histone
    deacetylation.31 Valproate has also been used in the
    treatment of EBV-associated tumors based on its ability
    to modulate EBV gene expression.31 Increased levels of
    EBV antibodies were also marginally associated with an
    increased prevalence of cigarette smoking.

    doi:10.1093/schbul/sby164

  • Last year the “Maven” Bruce D. Trapp

    Said:

    Microglia are in the brain to protect it and they
    do so through several mechanisms. Phagocytic removal
    of debris is fundamental to slowing the progression of
    MS and other neurodegenerative diseases. Many brains
    in our MS autopsy cohort have lost over 30% of their
    volume and include significant cortical thinning.
    Amazingly, little cellular debris can be detected in these
    brains, which is indicative of the efficiency of microglia
    in removing cellular debris. Inhibition of microglial
    activation and suppression of debris removal would
    accelerate, not ameliorate, disease progression.

    Much, if not all, of the cortical damage in MS
    can be attributed to the microglial cell – No

    DOI: 10.1177/
    1352458517743094

    Today in this study he says

    microglia were found to structurally damage myelinated axons

    pHERV-W envelope protein fuels microglial celldependent
    damage of myelinated axons in
    multiple sclerosis

    Proc Natl Acad Sci U S A. 2019 Jun 18

    Caneco
    🙁

    • Good evening,

      As an MS patient who is currently experiencing lots of MS activity. Burning, gnawing & neurological pain that makes you feel sick in neck and brain stem. Along with tinnitus, normal everyday neuro pain in arms, legs and head. Difficulty walking and heavy legs with numb heel, back of leg & balance issues. I’m astounded that our health history, nearest family too – isn’t documented & used to support research and hypothesis. Surely MS Society, MS Trust & all the other charities & fund raising options from patients groups etc – can support research & ideas? What is the money being used for? We don’t have time – time is being wasted in the NHS (i see it on my frequent visits to GP, hospitals and clinics) – it makes me want to scream that there isn’t any other medication to help with all the problems patients have and more understanding with the disease from healthcare workers. I’m constantly educating staff about what is happening to me and I get no real (I’m just a number) support. There isn’t any and we as patients deserve better than that. We have the resources albeit that they are being abused or used in wasteful ways. No-one should have to go through daily pain and be given no hope of a cure or trial that would support all what you guys are saying.

      I know things are happening to me – I can give you a list of things that have changed that indicate that the disease is highly active at the moment. But my only option is DMD’s – but they suppress it possibly for a while or until another part of the body start to go wrong from the aggressive drugs being used to prevent relapse. Pharma must take on more responsibility than offering DMDs – what about pain relief, what about giving patients hope that they are investing in looking at a cure for MS or at least preventing someone getting it if they have a particular virus or protein that can be altered by meds.

      Jane

      • Jill Piggott‎
        para
        National Multiple Sclerosis Society
        20 de janeiro de 2016 ·

        $430,826. That’s what the president of the Nat’l MS Society earns each year. I think that’s obscene and outrageous. My father, who died of MS, worked so hard to raise money for the Society, even when he was in terrible pain. My grandmother, who had so little, wrote checks, hoping something would be found to save her son. I was a volunteer fundraiser as a kid, and I’ve donated as an adult, but I’m done donating to the National Society. Why should I bother? Every donation I could possibly make would be sucked up in Cyndi Zagieboylo’s salary.

        I will find other ways to help people suffering with this disease, and I hope that others who have family members with MS will protest Ms. Zagieboylo’s annual salary of $430,826.

        I’m really angry about this, and I am writing this in honor of my beloved father, John R. Piggott, of Hopewell, NJ, an MS “Father of the Year” and local chapter board member. He would be furious to know that the Society is spending close to a HALF MILLION dollars every year on 1 person.

        It’s a big country, and there are lots of talented people. Surely the Society can find someone to lead the organization who’s willing to work for a non-profit at a fair wage. Cyndi Zagieboylo ought to be ashamed, and the Society really needs to rethink its direction.

        I’m angry. I hope others are, too.

        https://www.facebook.com/nationalmssociety/posts/430826-thats-what-the-president-of-the-natl-ms-society-earns-each-year-i-think-t/10153484099289315/

      • cynthia zagieboylo salary 527 970 us dollar

        President of ms society of the Usa

        Paul weiss chief operating officer 325 586 us dollar

        Tami caesar 233036 us dollar
        Cfo

        Eric hilty 220 706 us dollar
        Clf

        Tim coetzee 320 656 us dollar

        Cro

        Graham mcreynolds 311 049 us dollar

        Jonh scott 315 086 us dollar

        Cfo

        Maureen reeder 269 252 us dollar
        regional evp

        Jennifer lee 233 310 us dolar

        Regional evp

        Phyllis robsham 238 273 us dollar

        Regional evp

        Kay Jullian 221 276 us dollar

        Evp,services

        Lisa golfarbb 231 301 us dollar

        Evp human resources

        Compensation of current oficers ,directors,trustessand key employee s

        2 510 223 us dollar

        Other salaries and wages 64 906 676 us dollar 😦 😦 : (

        https://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Financials/2017-990-IRS_Final.pdf?ext=.pdf

        Grande regabofe 😦

        When you donate to the ms society know where your is going to

        • Wow, those salaries are eye watering, even more so when summed. Where is the money coming from? Surely this isn’t all fundraising revenue? Money from big pharma? Nevertheless, it shows you where their priorities lie.

        • A very astute man in Canada went through the financials of the MS Society, which are of public record. Only 14% (14 Cents Out Of Every Dollar raised) went to actual MS research.

          There is a good reason that they are one of the lowest rated charities worldwide. It is nothing more than a self-propagating big business with heavy ties to Pharma and their associated puppets.

          • I gave up giving to charity a couple of years ago when I read that the CEO of Save the Children earned $300,000. A friend worked for another large top 10 charity and saw the other 9 as ‘competition’. MS charities produce lots of glossy leaflets, but like most charities are interested in fundraising. If the delivered on their objectives (irradiating MS etc) they would be out of business.

    • “Inhibition of microglial
      activation and suppression of debris removal would
      accelerate, not ameliorate, disease progression.”

      True, microglia need regulation (harder), not inhibition. But MS researchers have a one-track mind to deplete. Better wait for Alz. research on microglia.

  • I really don’t know how when this is going to change. I am also tired of doctors who go only by the book. I have meet some of them . Never mind what you say they will not listen if it is not in the book. One example i was told to stop Fingolimod 2011 by then there were few publications mentioning rebound effect, i am a scientist i new what i was talking about , i was totally dismissed they were following protocols, my immune system went back to normal and I had a major relapse I never recovered from. When i could still walk i was denied fampridine sativex stem cells…..protocol says no.

    I have to thank so much Barts. With Cladribine I have hope now. Shame I didn’t know about it before…

  • The UK MS Society is funding physiotherapy for people with MS in my area. This is a huge help for me and many others. So not all MS Societies are simply fumbling funding juggernauts.

    • Good they are doing that but does seem that it would be good if we could raise money for the scientists and clinicians to directly fund research that they know could make a difference right now. Problem with charities is that they can become as much about their own survival as the cause they exist for – and also become vulnerable to all the ‘politics’ that other organisations get immersed in. Sometimes this is why big donors cease their involvement with a charity and eventually the cause.

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