Friday, 27 February 2015

CrowdSpeak: the rationale behind Charcot 2 or the HEART study

What is the rationale behind the HEART trial? #CrowdSpeak #MSBlog #MSResearch

"Some of you have asked about the scientific rationale behind Charcot 2. If you have been reading this blog for sometime you will have noticed a theme emerging around viruses and MS. There is now compelling evidence that EBV and HERVs (human endogenous retroviruses) are involved in MS. Some of us in the community are of the opinion that EBV causes MS and that if you can prevent people becoming infected with EBV you may prevent MS. How EBV causes MS is not known and there are as many theories as there are investigators working in the EBV-MS field. I personally 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 immun 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 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 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, or two, or even three, swallows don'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. We have also asked  the Swedes, the Kaiser Permanente (California) and the Veterans Administration (US) to look at their databases to see if they can confirm our observations. 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 HEART 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 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?"

"The survey is still open and we have expanded the number of questions we are asking; we need more responses in relation to the type of funding model and whether or not you you understand what we are trying to do."

"Please note although we are going with the Charcot 2 Project we are still working on the  HSCT vs. Alemtuzumab or the ZEUS study. At the moment we are engaging with Dr Paolo Muraro's group at Imperial who will need to lead on this." 

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

CoI: multiple


  1. Prof G- why don't you get prof gold to sell this- it is his baby

  2. Prof G, just use your Big Pharma contacts to fund you and call in a few favours. You've done a lot for them, get them to put their hands in their pockets. Big Pharma has tons of money.

  3. Prof G,
    If you confirm viruses as the cause of MS would a antiviral therapy work purely on a preventative basis or would it also help people who already have MS?

    1. What this guy said^^
      Prof G? MD 1 or 2??

    2. What this guy said^^
      Prof G? MD 1 or 2??

    3. Re: "Prof G, If you confirm viruses as the cause of MS would a antiviral therapy work purely on a preventative basis or would it also help people who already have MS?"

      I think viruses are driving the disease; therefore antiviral will work as a DMT.

    4. Hi Prof G,

      Let's say the first set of clinic trials is positive and viruses are the cause of MS...

      Would it be very risky if MSers started taking antivirals daily as a precautionary measure?
      Or is this something you would not recommend for whatever reason?

  4. Proff G when is the Inspire Study report , I can't wait to see the results !

  5. Great explanation - thanks Prof G! I'm excited to get things going ASAP now. When can we start and how much do we need for the 'heart trial'? Not sure I love the name as this really has very little to with the heart but similar options aren't amazing either (CHEART, CEART). On second thoughts maybe the HEART trial does sound better ...

  6. Fingers crossed there's good sogns with raltegravir! although I did think HEART may have been a better choice for the first trial going on the data

  7. When will we see data from "the Swedes, the Kaiser Permanente (California) and the Veterans Administration (US)" ?

  8. I believe the Charcot project 2 would be the preferred choice as stated before there is a lot of ongoing trials for hsct which maybe could be learned from before you partake in a trial.
    However why are we not hearing more about the initial Charcot project trial? I personally think your on to something with the theory, it just makes sense
    There is a young lad on another forum who had Ms then diagnosed with hiv, once he started treatment for hiv, he found his symptoms subsided


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