MS Trust Talk 2012 - Kenilworth, UK

The following is my presentation from yesterday's meeting (4th November 2012) for you to watch and download. 

The main messages from my talk are:

  1. The immunology of MS is complicated and we cannot be sure what the main drivers of the abnormal immune response are. For example we don't even know what the auto-antigen in MS is! There is evidence for involvement of the innate (hard-wired) and adaptive (memory) arms of the immune system. If I was to put my money on key players I would say the most important targets are B cells & plasma cells, these are  the cells that produce antibodies. Other important cells are CD8+ cytotoxic and NK cells, which primarily target viruses.
  2. MS may not be an autoimmune diseases, i.e. the inflammation in MS is secondary - the inflammation occurs in response to what is causing MS. Evidence I provided for this was:
    • Changes on MRI, in particular MTR, precede new focal lesions by several weeks, implying that some changes occur in the "normal appearing whit matter" prior to the development of inflammation as measured by Gd-enhancing lesions on MRI.
    • There are many pre-inflammatory lesions in MS, i.e. clusters of activated microglial cells that don't have any T-cell infiltrates.
    • The Barnett & Prineas lesions; these lesions show extensive oligodendrocyte death or apoptosis (programmed cell death or suicide) without a T-cell inflammatory infiltrate. We now think these may be the initial destructive lesion in MS. The million dollar question is what is killing those oligodendrocytes? Could it possibly be a virus?
    • The observation that aggressive immunotherapy, which stops relapses and MRI activity, does not necessarily stop progressive disease. In other words is progressive MS independent of inflammation? We will know the answer to this question from the long-term follow-up of alemtuzumab treated MSers. If alemtuzumab-treated MSers stay in long-term remission (>15-20 years) then we can assume that inflammation is the probably the primary driver of the inflammation. If on the other hand these alemtuzumab-treated MSers come back with secondary progressive MS, I would interpret this as indicating that the inflammation in MS is secondary and, therefore, MS should be classified as a primary neurodegenerative disease. This topic has been covered in one of my previous grand challenge posts: Grand Challenges in MS (2): early aggressive therapy, 06 Jul 2012.
    • I also discussed the rebound or syndrome of fulminant MS that occurs after the withdrawal of natalizumab. In MSers on natalizumab, is the cause of MS allowed to go unchecked by the immune system and that when natalizumab is stopped the immune system is allowed to find what is causing MS and attack it? This is similar to what happens in PML with IRIS (immune reconstitution inflammatory syndrome). Could rebound be due to the immune system attacking the virus that causes MS? Could the rebound used as evidence that MS is caused by a virus; i.e. reasoning by analogy?
    • I used the hypothesis that MS is possibly caused by a virus to introduce the Charcot Project and explained that the main purpose of the Charcot Project is to explore the viral causation theory by testing antiviral treatments in MS. The viruses that Charcot Project are initially targeting, are EBV and HERVs (human endogenous retroviruses). The good news is we have funding to start a trial in the New Year; once things are more certain we will announce the trial and drug on this blog.
  3. The greatest unmet need in MS is progressive disease: we have identified number of therapeutic targets for progressive MS and a large number of potential drugs that work on these targets. The main problem at the moment is poor trial design and the persistent use of EDSS as a primary outcome in progressive trials. The EDSS is simply not fit for purpose when it comes to progressive MS; i.e. it is not responsive enough to allow trials to be done in a reasonable period of time. I used the CUPID study to illustrate this point; 560 progressive MSers followed for 3 years gave us a negative result. However, when you analysed those MSers who had an EDSS  lower than 6.0, i.e. on  a part of the EDSSS scale that is responsive to change, THC (the active ingredient from cannabis) the delayed progression. Have we thrown away an effective drug because of the EDSS and poor study design? Maybe! What we now need to do is learn from the CUPID study and improve on our trial design. This then led onto a discussion on two new trials that are currently addressing neuroprotection in novel way. The spinal fluid neurofilament trial and the acute optic neuritis trial; if you are regular readers of this blog you will be aware of both of these studies. Please see these previous posts:

    Multiple Sclerosis Research: Name that neuroprotective trial
    Would you consider having a lumbar puncture as part of a ...
    Research: Lumbar punctures- BlogG to the Publishers
    Neuroprotection With Phenytoin in Optic Neuritis

  4. Finally, I spent some time talking about the MS endophenotype. The MS endophenotype is the concept that MS develops many years before you become aware of it. The concept of the endophenotype underpins our current work on trying to identify people at high-risk of MS so that we can prevent the disease. The main targets for prevention are vD/sunlight, EBV and smoking. You will have heard me going on about this like a stuck record on this blog and I will continue to do so; it is that important to me! We are in the process of trying to get funding to take this concept forward. Unfortunately, the reviewers' / the field, at least in the UK, don't seem to be ready for prevention yet. This would change if we could only get our Predict-MS study funded.

The following are the two embedded videos that are shown on slide 23. These show how axonal plasticity allows a demyelinated axon to resume conduction. It is clear from the second video that it takes a lot of energy to conduct an electrical impulse down a demyelinated axon. This axon is vulnerable to degenerate from an energy deficit and too much calcium that enters the axon as a result of excessive sodium entry into the axon. We and others have shown  that if you reduce conduction down these axons with a class of drugs called sodium channel blockers you protect them; possibly long enough to allow to be remyelinated, which enables them to survive so that the animals with an MS-like disease do better. Both our current neuroprotection studies are using sodium channel blockers. 

CoI: multiple