Sunday, 11 February 2018

My trip to Lucerne and the Charcot Project

A few weeks ago I was invited to give a lecture at the annual Swiss MS Society meeting on 'The Charcot Project' and the rationale behind using anti-viral drugs to treat MS.



As promised my slides from the meeting; they should be self-explanatory:






The Charcot Project is an initiative that Professor Gold and I launched about 5 years ago to tackle MS from a different perspective; a perspective that MS is caused by a virus and to tackle MS we need to start doing treatment trials using anti-virals. The two leading viral contenders are EBV and HERVs.  If you have any queries about the slides please feel free to ask. 

In this presentation, I stress the point that I have made several times before that MRI activity (new Gd-enhancing lesions) and relapses are not MS, the disease. If they were the disease they would predict MS outcomes whether or not you are on a DMT. The data indicates they only predict outcomes when you are on a DMT. Based on Prentice criteria of what constitutes a surrogate end-point for a disease both relapses and MRI activity fail. 

I then review the observation that changes occur weeks to months in the white matter before a new focal lesion occurs. This would indicate something is happening in the brain of pwMS prior to inflammation ('Field Hypothesis'). This may explain the Prineas lesion, i.e. oligodendrocyte apoptosis without overt inflammation. The million dollar question is what is killing the oligodendrocyte? 

I then review the epidemiology evidence supporting EBV and possibly HERVs as the viral aetiology of MS. I complete the lecture with some experiments that need to be done to prove that EBV is the cause of MS. Simple? I wish! Trying to get funding for studying the viral cause of MS is very difficult and slow, but we will get there, eventually. 

ProfG    

18 comments:

  1. Hello ProfG,

    I have MS and I have been taking 1gram of valacyclovir three times a day for 4 years now in hopes that it will do something for me. A few questions:

    1. How does this differ from the 3 different trials already done using treatment dose valacyclovir/acyclovir in MS?

    2. What dose of famciclovir will you be using in this trials?

    3. Do you think long term antiviral use will do anything to the EBV reservoir in the B cells? There is one study showing that long trrm use of valacyclovir can eliminate EBV infected B cells after 6-12 years of long term antiviral use. Maybe adding simvastatin might help with this as it causes apoptosis of EBV infected B cells at concentrations over 2 micromolar. Thoughts?

    ReplyDelete
    Replies
    1. Re Anon 3.43 simvastatin

      I didn't know that. Made me curious:

      www.ncbi.nlm.nih.gov/pmc/articles/PMC387356/

      80mg dose, sounds familiar... maybe that's how MS-STAT worked...?

      http://multiple-sclerosis-research.blogspot.com/2017/05/how-do-statins-work-in-secondary.html?m=1


      Delete
  2. I take valacyclovir 1000 mg

    It does not rid you from ebv

    If you read the instructions it does not mention Ebv

    Obrigado

    ReplyDelete
  3. "Trying to get funding for studying the viral cause of MS is very difficult and slow"

    Isn't there any other (cheaper) way to test the viral hypothesis without doing (another) trial with antivirals? Trials are too expensive to be used as research tools.

    -Have you tested the viral hypothesis against everything that is known about MS?
    -Did you try to disprove it?
    -Which aspect of MS does the viral hypothesis explains better that other theories?

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  4. Slide 5 is exquisitely beautiful. Thank you Gavin on My trip to Lucerne and the Charcot Project

    David Stratton
    at 20:13

    Plea

    ReplyDelete
  5. What is the next step for the Charcot project? Could you do some more crowd funding to help thing along? I'm sure there are many people in the community who would happily contribute something to advance our understanding of what's going on with this disease.

    ReplyDelete
  6. Could Charcot have an unfolding and have a parallel research that actually linked MS to EBV or Hervs acting according to certain genetic mutations?

    One of the slides of the presentation shows a possible link between HLA mutations and IM.
    I think it's slide 28.

    ReplyDelete
  7. A study on the effects of valacyclovir in multiple sclerosis did not show any significant results

    A randomized clinical trial of valacyclovir in multiple sclerosis.

    https://www.ncbi.nlm.nih.gov/pubmed/15957509

    Also, this book argues about it (Immune Regulation and Immunotherapy in Autoimmune Disease)
    https://books.google.gr/books?id=gCKIXurUh9sC&pg=PA206&lpg=PA206&dq=Valacyclovir+ms&source=bl&ots=IErT1XvsA0&sig=OpeaHWTwCVp3J9XNY7s-0ei1kJE&hl=el&sa=X&ved=0ahUKEwjhkcnBuKDZAhVEiKYKHXY6DNg4ChDoAQg0MAI#v=onepage&q&f=false

    Famciclovir seems more effective at controlling EBV than valacyclovir.


    Also, L-Lycine (which is a component of Copaxone) and is used by patients who have EBV exacerbations has only one study -that I could find- and is not a good study

    https://mospace.umsystem.edu/xmlui/handle/10355/1565

    ReplyDelete
  8. Acyclovir and the prodrug form (gancyclovir or valcyclovir) do not have any effect on latent EBV infection. They can block lytic replication, but there is not anything that blocks the latent form yet.

    ReplyDelete
  9. This is a very well thought out assay

    However there is some "gaps"

    In slide 42 you consider that most ms dmt´s limit memory b cell to

    enter cns, next in slide 47,48,49 you talk about hiv and the fact

    that people with hiv dont hab«ve or dont feel ms

    You reason thats due to the Art theraphy

    As you know CD4+ T cell depletion and immune activation are hallmarks of HIV infection

    So Hiv should be the mother of all immunne supression regimes those

    that last your lifetime ,so maybe its the immunne supression

    ,not Art theraphy ,thats controlling ms

    In Hiv Ebv is related to the Cd4+ cell population

    Also during hiv infection infection Ebv load rises even if you are on

    Art theraphy

    "During HIV infection PBMC-EBV load rises in comparison to healthy carriers, but decreases when immunosuppression progresses and CD4+ T cell count becomes <50/mm3. Circulating EBV is mainly cell-associated in the HIV-infected population. Neither PBMC-EBV nor plasma-EBV loads would be useful to diagnose brain lymphoma in AIDS patients."

    https://www.sciencedirect.com/science/article/pii/S1201971206000841#bib4

    Obrigado

    Luis

    ReplyDelete
  10. Here in Brazil I know, in particular, a case of a person with HIV who later developed MS.

    There are other case reports described in studies, so probably Dr.Gold and Dr. Gavin may be right yes, antiretrovirals may be containing something in MS when it exists in conjunction with HIV infection.


    https://www.omicsonline.org/multiple-sclerosis-like-demyelination-in-early-hiv-infection-a-rare-presentation-case-report-and-literature-review-2155-6113.1000124.php?aid= 1731

    ReplyDelete
  11. What do you think about Spironolactone
    as treatment against EBV ?

    ReplyDelete
    Replies
    1. About Spironolactone

      Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-α and interferon-γ, and has potential in the treatment of arthritis

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808828/


      Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function.

      https://www.ncbi.nlm.nih.gov/pubmed/26976570

      Delete
    2. Let me break it down why spironolactone won't work for your ebv and just give you kidney and hormonal side effects.

      In terms of how strong an antiviral spironolactone is against Epstein-Barr virus, the in vitro study on the antiviral effects found that the IC50 of spironolactone occurred at a concentration of 2.1 μM (IC50 is a way of measuring antiviral efficacy).

      But this pharmacokinetic study found that in humans, an oral daily dose of 100 mg of spironolactone produced a peak blood plasma concentration of 80 ng/ml ( = 0.19 μM), and short half-life of 1.4 hours. (Looking at spironolactone doses, 25 mg to 200 mg daily are typically used).

      So 0.19 μM is the concentration of spironolactone in the blood after daily oral dosing of 100 mg daily.

      But in the blood, spironolactone is around 90% bound to plasma proteins, and it is only the 10% free unbound spironolactone that has an active effect. The plasma concentration of free spironolactone is just 0.019 μM. This concentration is far too low to have a useful antiviral effect in the body, since the in vitro study found the IC50 antiviral concentration that we have to aim for is 2.1 μM.

      So the bottom line is that when you take it orally, spironolactone is a weak EBV antiviral, and is not likely to be much help for EBV.

      Even the study authors know this: "According to Swaminathan, in its current form, spironolactone is far too toxic to use for treating the herpes virus and its side effects range from compromising kidney function to increasing secretion of salt. However, the team is confident that they will be able to separate spironolactone’s heart failure properties from its antiviral properties, making it not only effective but also safe for use."

      Delete
  12. Is there any utility in MS patients monitoring their EBV titres?

    ReplyDelete
    Replies
    1. Following this question

      http://multiple-sclerosis-research.blogspot.com/2011/11/herpes-virus-6-linked-to-ms-relapses.html

      http://multiple-sclerosis-research.blogspot.com/2014/03/ebv-re-activation-in-relapses.html

      Isn't it important that such studies to be extended?

      Delete
  13. N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724866/

    "EBV infection can lead to multiple post-viral inflammatory conditions as well as being a risk factor for auto-immune disorders including MS and SLE. The viral-encoded protein LMP1 is a potent inducer of inflammation [30], which may be at the root of many of these post-viral syndromes. Non-steroidal anti-inflammatory drugs are extensively used in the treatment of such conditions. Here, we have investigated the use of an anti-oxidant to boost the body’s inherent redox regulatory mechanism, in an attempt to break the feed forward loop between oxidative tissue damage and inflammation, which could persist after the virus departs."

    ReplyDelete
  14. ProfG posted this

    We present the case of an HIV-negative patient clinically diagnosed with relapsing-remitting MS who achieved significant disease improvement on Combivir (zidovudine/lamivudine). Within months of treatment, the patient reported complete resolution of previously unremitting fatigue and paresthesiae, with simultaneous improvements in lesion burden detected by MRI. All improvements have been sustained for more than three years. This response may be related to the action of zidovudine as a known inhibitor of EBV lytic DNA replication, suggesting future directions for clinical investigation.

    Could antiretrovirals be treating EBV in MS? A case report.
    https://www.ncbi.nlm.nih.gov/pubmed/29510325?dopt=Abstract&utm_content=bufferaf5bf&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer


    Wheelchair Kamikaze had done some research on AZT zidovudine at this post
    http://multiple-sclerosis-research.blogspot.com/2017/11/the-season-of-ms-glandular-fever-may.html

    ReplyDelete

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