Monday, 13 April 2015

CrowdSpeak: EBV, vitamin D & genomics

It's about time we got ARTEMIS off the ground. #ClinicSpeak #MSResearch #MSBlog

"The study below links EBV and vitamin D (vD) genomics to MS genomics and proposes that all these risk factors interact with each other at the level of the genome to cause MS. The EBV gene EBNA2 binds human D at numerous locations and this study demonstrates that these sites are enriched for vD binding sites and areas of the the genome where genomic variants are associated with increased susceptibility to MS. This is really a descriptive study and does provide mechanistic data to support the claim that 'these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS'. Despite this criticism, this study is important and provides a link between three important risk factors and hopefully will trigger research to pin down the mechanistic links between environmental and genomic risk factors in MS."

"In my opinion the evidence that vitamin D and EBV are associated with MS is beyond reasonable doubt. What is lacking is the evidence that this association is causal. To be honest with you the only way to prove causation is to do well controlled definitive trials. With regard to vD this will involve both vD prevention and treatment trials; unfortunately, I am sceptical that the current treatment trials will work as they are underpowered and don't involve treating to a specific vD level. The prevention trials will need to be done at a population level and will take 2-30 years to read-out. With regard to EBV there are two, and possibly three, strategies; (1) EBV vaccination studies to see if preventing wild-type EBV infection prevents MS and other related autoimmune diseases; (2) treating MS with drugs that target EBV (we are hoping to do the latter) and; (3) treating infectious mononucleosis, or glandular fever, to see if can prevent the autoimmune complications associated with symptomatic EBV infection. For the latter two strategies we need to test anti-EBV drugs. Apart from rituximab (anti-CD20) there are no licensed anti-EBV drugs. This is why we are trying to get funding for our ARTEMIS study. The ARTEMIS study will provide us with the necessary data to test our proposed anti-EBV drug in both MS and IM."

"For those of you who follow the blog regularly will have heard that we have now found a crowd funding partner to take on the task of raising funds for a second proof-of-concept trial under the Charcot Project umbrella. You the community who suggested the crowdfunding route, voted on the project (Charcot project vs. ZEUS Trial), and have given the trial its name (ARTEMIS - Anti-Retroviral Treatment for Epstein-Barr Virus in MultIple Sclerosis). We are in the process of resolving some of the final questions about the trial design."

"Our Crowd Funding partner is called CROWDACURE; who plan to launch the crowd funding campaign in about a 6 weeks time."

"This remains a community project so please feel free to comment. Thank you."

Ricigliano et al. EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy. PLoS One. 2015 Apr 8;10(4):e0119605. doi: 10.1371/journal.pone.0119605. eCollection 2015.

Background: Epstein-Barr virus (EBV) is a non-heritable factor that associates with MS. However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. 

Objective: To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development) binding inside MS associated genomic intervals. 

Results: We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). 

Conclusion: Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.

CoI: multiple


  1. Is there a reason that you guys are looking into this when you currently have the charcot project working?

  2. Dear ProfG team, I am an italian mser, following your blog since my diagnosis at the beginning of 2014.
    I have a couple of questions for you:
    1) Will be possible to fund this project for foreign people?
    2) Same question as Anon. 09:30:00 am; shouldn't Artemis be planned also on Charcot feedback/results?

    Thanks in advance for your reply and best regards from Italy....

    1. RE: "1) Will be possible to fund this project for foreign people?"

      Yes, almost certainly.

    2. Re; " 2) Same question as Anon. 09:30:00 am; shouldn't Artemis be planned also on Charcot feedback/results?"

      Yes and No. If the INSPIRE is positive that will give us some data to press ahead with HAART. If negative it does not disprove the hypothesis as raltegravir was launched after the period during which we have shown an impact of HIV on MS incidence. Raltegravir also works downstream of HERV activation. In addition, we need to test anti-EBV in combination with HAART to see of they synergise. We are planning ahead so as not to delay things. Almost certainly the INSPIRE trial results will be available before the ARTEMIS study gets going.

    3. I hope we Brits don't come out of the EU, but will it make a difference to research if we do?

  3. Vitamin D is bad for one's health, though:

    1. Odd how all the ifs and buts disappear between the journal paper, the press release and then the internet article. The vast majority of the people in the study were deficient and only a small number had above average, so the 247,574 people in the study is not the sample size for this article. The sample size for those above 125 nmol/L was 3,698, so this the population that showed a small apparent increase in risk, however, the small numbers of deaths in this group makes the results less certain. The greatest failure is to not ask why they are higher, and I would propose that it is because sick people take vitamins and healthy people do not. So the sample is not random and high vitamin d levels are a measure of pre-existing illness either treated by a doctor or self medication.

    2. To Anon at 11.58am
      I have seen the study which was linked to the Yahoo article, and looked a bit deeper into it. I noticed that the researchers seemed to only look at Vit D levels in isolation. I am a very very long way off being any sort of expert, but when I was a good compliant little MS patient I took the high doses of Vit D which I was recommended to and had some problems. After investigating further I found that taking large doses of Vit D in isolation was not the great idea that it is promoted as, and that there are other key things which need to be in balance otherwise Vit D can stuff up (technical term) your magnesium and calcium and a few other things, and that these can have an impact on your cardiovascular risks.

      As with so much on the internet these days, it is wise to look further than just one website for your info. With the strong focus on Vit D levels these days, many people are just taking lots of Vit D, including many MSers. Have a look at the Vit D Council's webpage on what else your body needs to ensure that the Vit D you do take is of benefit to you.

  4. Who is "Crowdacure"? How do you know them? What do they get out of it? Why do you want our cash when the MS Societies' are better research sponsors?

    Transparency, please.

    1. Re: "Who is "Crowdacure"? How do you know them?"

      I will get the founder of CrowdaCure to do a post. They found us.

    2. Re: "Why do you want our cash when the MS Societies' are better research sponsors?"

      The UK MS Society does not really have enough money in their funding rounds to fund clinical trials.If they did they would have very little for other grants. Sadly we failed at the Wellcome Trust and MRC; not because the grants go low scores, but dichotomous scores. Some very high and others very low. The low scores were from reviewer's who simply don't buy into the viral hypothesis of MS. C'est la vie.

      The crowding funding idea was not mine but came from the commentators on this blog. I personally still feel uncomfortable with it.

      I note a US based research project just got fully funded via a crowd sourcing platform. So it is possible if there a will to make it happen.

    3. Why do you feel uncomfortable? We are just trying to gather the necessary data to persuade pharma to take on a large scale trial.

    4. Hi, and thanks for asking!
      My name is Sagit Weiss, and I am by training a medical doctor and a immunologist. I worked with Prof G in the past, and also with other MS experts. When I met Timo Tuominen, a web developer, he was looking for a project with social impact. He wanted his work to make social good.
      We created together Crowdacure, a crowdfunding platform for difficult to fund medical research, precisely like this research project, ARTEMIS.
      BY focusing on difficult to fund projects we want to avoid redundancy with the excellent and hard work made by existing organisation in funding medical progress. We want to help take this further with the help of the people.
      Crowdacure is an enterprise based in London, we launch in May with 3 research projects in 3 different fields of medicine.
      Transparency is very important for us as this can happen only when the community is a partner.
      Is this helpful?

  5. Great stuff prof Giovanni
    It's good to see you guys are pressing ahead so as to not delay things, would these been seen as a phase 2 trial?
    Also is there any idea of when the Raltegravir charcot trial will result?

  6. Prof G and other Docs forgive my ignorance, I lay on the subject, but what are the necessary examinations to EBV infection detection? Will we one day they will become part of the routine tests for the diagnosis of MS, as well as vitamin D3 dose in the blood?

  7. I have often wondered if the incidence of MS is higher amongst submariners (popularly known as sundodgers in in Royal Navy "Jackspeak") than in the surface fleet. As an ex-submariner I've spent more than 1 year of my life dived. To my knowledge we were never given any vitamin D suplements.

    1. Hmmmm, don't know the answer to this but have been wondering the same regarding coal miners as both my grandfathers were (though neither had MS).

  8. I would gladly personally find HAART therapy for myself on a compassionate basis should you be able to assist
    I have had glandular fever recurring and had it last year which led to the onslaught of Ms symptoms I am currently having, please could you contact ME or provide me with details to contact yourselves


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.