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.