Monday, 9 March 2015

CrowdSpeak: ARTEMIS - we have a name for Charcot 2

Did you know ARTEMIS is Greek moon goddess portrayed as a virgin huntress? #CrowdSpeak #MSBlog #MSResearch

"The community has spoken; ARTEMIS received approximately 50% of the votes out of the proposed name for the Charcot 2 enabling trial."


ARTEMIS - Anti-Retroviral Treatment for Epstein-Barr Virus in MultIple Sclerosis




"Did you know that ARTEMIS is a Greek moon goddess often portrayed as a virgin huntress. I like the play on huntress; the primary aim of the Charcot Project is to hunt down the viral cause of MS."


"There is emerging evidence that EBV and HERVs (human endogenous retroviruses) are involved in MS. Some of us in the MS community are of the opinion that EBV causes MS and that if you can prevent people becoming infected with EBV you may prevent MS. I don't know how EBV causes MS. One of the theories that we are investigating is that EBV causes MS via its interaction with HERVs."

"HERVs are viruses that live in our genome; about 6-8% of the human genome is HERVs. Why do we have so many HERVs in our genome? Evolution has selected for them because they must give us, and other mammals, a survival advantage. For example, one HERV protein is critical for the development of the placenta. Mammals who don't have a placenta (marsupials) don't have this HERV. As HERVs are sort of 'foreign', the human body has developed intricate ways of detecting them and if they are found to be expressed in a cell the cells immune system flags that it is infected with a virus so that the immune system can eliminate the cell. This so called danger signal is often is what is needed to activate the immune system and if this happens to be an autoreactive immune cell it can trigger autoimmunity. Interestingly, there is a very rare disorder due to mutations in the systems that detect and suppress HERVs in cells. The children with these mutations present with multiple autoimmune diseases indicating that uncontrolled HERV expression can drive autoimmune disease. You may be aware by now that there is emerging data that MSers have evidence of increased HERV expression in the cells of the peripheral blood and possibly in their brains as well. At present we don't know if MS causes HERV expression or does HERV expression cause, or drive, MS? This is one of the reasons why we have launched the Charcot project."


"So how do EBV and HERVs relate to each other? It turns out that herpes viruses, in particular EBV, are potent transactivators of HERVs. In other words EBV does something to wake-up the sleeping HERVs  in our genome and increases their expression. This is the rationale for using drugs to reduce EBV activity in the hope they will suppress HERVs, or even better drugs that target both EBV and HERVs."


"Why HAART (highly-active antiretroviral therapy)? This is based on our anecdotal evidence that MSers who have become HIV positive and go onto HAART do well regarding their MS. We agree that one swallow doesn't make a summer, which is why we have done other studies to try and confirm these observations. What we have shown is that people who are HIV-positive and go onto HAART have a low risk of getting MS. The longer they are on HAART the lower their risk of getting MS is. We are not the only ones to observe this; the Danes have made a similar observation in their country. The big question is it the HIV virus or the HAART that is lowering the risk of MS? We don't know."


"However, once you make an observation like this you can't ignore it. This is why we have done the INSPIRE trial using raltegravir an antiretroviral drug that blocks the integration of retroviruses into the genome. Raltegravir is a relatively new anti-retroviral, and was only launched in 2009 and only becoming widely used in the UK to treat HIV-1 infection from 2011.  The latter is important because our observations of HAART lowering the risk of getting MS was from the pre-raltegravir period. Therefore, regardless of whether or not the INSPIRE trial is positive we need to test HAART as a potential treatment for MS."


"I am aware that what I am saying above is complex, but I hope it sets out the rationale and makes the case for using both and anti-EBV drug and HAART in MS and more importantly for using them in combination. The proposed ARTEMIS study below is simply and enabling study to provide us with necessary virological and safety data to make the case for doing a larger efficacy study in MS."



"As you can see there are still many questions that need answering and we would like your input to answer them. The purpose of this study is to explore whether or not our candidate drugs do what the meant to do to on the target viruses in MSers and to show that there are no major safety issues. Further thoughts please?"



"We have opened to following survey for you to help us design the study."




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


CoI: multiple

18 comments:

  1. Where are you wih regards to funding of this trial at the moment? Also what happens to patients if they find success on the HAART therapy? Are they able to stay on the drugs or do they stop once then trial is done

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  2. EBV is not a retrovirus - otherwise good idea!

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    1. What if anti-retrovirals have an effect on expression of HERVs? In MS if latent EBV induces HERVs leading to immune response then anti-retroviral may suppress this response. Why are there no patients on ARDs with MS? If the incidence in the U.S is roughly 1:1000 and 1.2 million are infected then we would expect 1200 or so cases of MS. Does this class of drugs prevent MS from developing by HERV suppression?

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  3. I think some of the questions in this survey really ought to based on best scientific rationale rather than a consensus opinion. The name of the trial is a perfectly reasonable thing to be asking the MS community but surely we need to think more carefully about who to include in the trial and their previous DMT exposure as this may potentially effect the results.

    Based on evidence to date it would seem that restricting the trial to patients with RRMS would give us the best chance of showing an effect. Also, based on previous arguments put forth on this site, it would seem unethical for a patient not to be on a DMT, however, given the extensive range of DMTs available these days how would we control for this in the trial? Having sub-groups of patient's based on their current DMT would make the trial too complicated, not to mention the additional expense of needing to ensure enough participants in each subgroup. However, if we don't control for DMTs somehow then how do we know any effect we measure is due to the intervention and not the DMT?

    It all gets quite complicated when actually start thinking about the practicalities!

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  4. "What"s in a name? A worthwhile trial by any other name will still be as sweet,"

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  5. Surely it's disgustingly ignorant to try to exclude people with ppms when the hypothesis includes all groups of ms?
    I think to exlude this group would be highly insulting to all involved and possibly only prolong the wait for a drug such as this for people with ppms

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    Replies
    1. No one cares about PPMS. PPMS has been devalued by being grouped as MS.

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    2. Maybe. I guess it depends on what outcomes we are measuring. If we want to measure reduction in relapse rate then obviously we need participants with a relapsing form of the disease. If we want to measure progression surely a 24 week trial is no where near long enough? Maybe we should be measuring something else altogether (MRI activity, biomarkers of damage, EBV/HERV expression) but do we know how these correlate clinically and do these parameters differ in different forms of MS?

      When you really start thinking things through you start coming up with millions of variables that could effect the result. Surely we need to keep the participants as similar as possible so that we can be confident than any effect we do show is down to the drugs?

      What do you think the outcome should be? How do you think we could control for the different forms of MS?

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    3. surely it is time to take a chill pill and read the post before flying off the handle:-).
      Not sure where the suggestion to exclude PPMSers is.

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    4. surely it is time to take a chill pill and read the post before flying off the handle:-).
      Not sure where the suggestion to exclude PPMSers is.

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  6. How long before this trial would produce any meaningful results???

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    1. a few years after the studies are funded

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    2. a few years after the studies are funded

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    3. MD,

      So realistically....for current MSers....

      Charcot & Charcot 2 will not really be able to help us until in say like 10 years time?

      Should we start gulping antiviral pills anyway at some point in these 10 years?

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    4. We have talked about the drug development time and unfortunately with the system as is there are no quick fixes.

      Should you start gulping anti-virals...the straight answer is no, because we do not know if they are of any use and we do not know if they are of any harm. There are many anti-virals. Which one or which ones?

      The profGs talka good game but what have they shown...We have said many times anecdote is no antidote or doing good science and therefore we have to practice what we preach.... don't we?

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  7. Is there any idea on when Charcot 2 will begin, I'm almost convinced this theory is correct and had the best chance to stop or slow progression
    Look at GeNeuro with gnbac1 for example

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  8. What is the level of funding require I would gladly self fund a portion of it if included

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