In response to a recent question; the following are my choices of the “big 5” questions that are currently being asked in MS research.
1. CURE: Can we cure MS by rebooting the immune system early in the course of the disease?
This question is currently being asked by treating MS’ers early in the course of their disease with drugs such as alemtuzumab and cladribine or with autologous bone marrow transplantation. We know these therapies often render MS’ers disease-activity free (no relapses, no MRI activity and no disability progression), however, will these treatments prevent these MS’ers developing secondary progressive MS? To answer this question we will need to wait about 15-20 years for an answer. If these treatments don’t prevent the secondary progressive MS then it is likely that MS is a primary neurodegenerative disease.
2. NEUROPROTECTION: Can we protect nerves and axons during acute focal inflammatory events, for example optic neuritis, or in progressive MS so that they can be saved to preserve function?
Several treatment strategies are currently being tested in clinical trials to answer these questions. If these trials are positive this will almost certainly lead to large combination therapy studies, with one therapy targeting inflammation and another therapy aimed at protecting nerves to maintain function.
3. PREVENTION: Can we prevent MS with physiological vitamin D supplementation?
The hurdles and logistics of doing the correct studies to test this hypothesis are enormous. However, I am confident that we will eventually get public health officials to see the light (sunlight) and to start a population-based food fortification study. The costs of not doing something are simply too high not to do something. Can we let a whole new generation of MS’ers be born?
4. CAUSATION: How do all the risk factors for developing MS interact with each other?
Over the last 20 to 30 years several genetic and environmental risk factors for developing MS have been identified. If we can work out how these factors interact with each other, and the timing of these interactions, we may have a better idea of how to prevent MS in people at high-risk of developing MS (siblings and children of MS’ers). Several research groups, including ours, are working on this problem. This research question gets to the heart of the cause of MS.
5. SYMPTOM MANAGEMENT: Symptomatic therapies for MS’ers are in general sub-optimal. In particular our ability to treat fatigue, cognitive impairment, spasticity and pain. Developing and optimising symptomatic therapies will have a major impact on the quality of life of MS’ers.
We are and others are working on symptomatic therapies. The solution to these problems, however, lie with big pharma. Pharma have the resources to best tackle these problems.
You will be disappointed, particularly if you have progressive MS, that I have not added restoration of neurological function to this list. The reasons for this are complex; firstly, I don’t want to raise unrealistic expectations (neurorestoration in the MS arena is a long way off) and secondly, the evidence that we can do this is poor at present. The improvement we see in people with highly-active MS going onto an effective DMT is probably due to recovery from natural mechanisms as a result of the particular DMT suppressing further damage, rather than the DMT triggering repair mechanisms directly. However, I remain open to the idea that some DMTs may have a dual action; on the one hand suppressing inflammation and on the other hand stimulating recovery. In my experience recovery of function tends to occur in MS’ers early in their disease course rather than later in the disease, presumably because compensatory mechanisms fail or burn out with time and possibly with age. The latter seems to a common theme across the spectrum of neurological diseases.
The holy grail of MS is neurorestoration!
I would be interested to know what you think of my “big 5”? Do you agree? If you disagree please tell me why?
No mention of EBV & HERV? I thought that's a big part of your research.Also, are causation and prevention two different questions? Prevention will come with or after an answer to causation.
Holy Grail n1. a. (Myth & Legend / European Myth & Legend) Also called Grail Sangraal (in medieval legend) the bowl used by Jesus at the Last Supper. It was allegedly brought to Britain by Joseph of Arimathea, where it became the quest of many knightsb. (Spirituality, New Age, Astrology & Self-help / Alternative Belief Systems) (in modern spirituality) a symbol of the spiritual wholeness that leads a person to union with the divine2. Informal any desired ambition or goal the Holy Grail of infrared astronomy [C14 grail from Old French graal, from Medieval Latin gradālis bowl, of unknown origin]Collins English Dictionary – Complete and Unabridged © HarperCollins Publishers 1991, 1994, 1998, 2000, 2003
Re: "No mention of EBV & HERV? I thought that's a big part of your research."Point 4; EBV and HERVs are tied-up in causation.
Regarding Cure; The earliest MSer's to be treated with alemtuzumab were in the 90's. Even if there were only a handful, have any of them progressed yet?Could it slow down progression to such an extent that it happened in 30-40 years rather than 15-20?Regarding neurorestoration; Are Charles ffrench-Constant and Robin Franklin likely to give any exciting news about the progress in this field at the Manchester meeting?Will it be on Youtube?
Re: "Regarding Cure; The earliest MSer's to be treated with alemtuzumab were in the 90's. Even if there were only a handful, have any of them progressed yet?"Some have progressed and I am told others have not, but overall there are too few MS'ers treated to be sure of the result. Let's wait and see. At some stage we will have to ask Alastair Coles to post on this issue.
Re: "Regarding neurorestoration; Are Charles ffrench-Constant and Robin Franklin likely to give any exciting news about the progress in this field at the Manchester meeting? Will it be on YouTube?"Not sure! Professor Robin Franklin is a mouse and rat doctor; treating rodents is not quite the same as treating MS'ers. I am not sure if Robin's work is ready for humans yet. I am aware of differences in rat and human biology that will need to be sorted out before trials can start in humans. Professor Charles ffrench-Constant works in close collaboration with Siddharthan Chandran. As you are aware Siddharthan has recently published his pilot study on autologous mesenchymal stem cells, which suggests that they may be neuroprotective. http://www.ncbi.nlm.nih.gov/pubmed/22236384I am not sure if the Manchester programme has been finalised and whether or not the talks will make it on to YouTube.
(first anonymous again): I think neuroprotection is the most urgent requirement and what is most relevant to people who have MS already. Progression is the worst part of MS
There are los and lots of people who would love the progression of MS to be stopped in its tracks. Not too sure which one of your 5 should be replaced 'cos they all seem fairly important
Prof G,I like your lists.As a recipient of Alemtuzumab, I'm hoping it keeps Secondary Progression at bay.The question to add is WHEN (will these other questions be answered).Prevention and causation – looks like another 10 years before these are answered. Cure by re-booting – you say 15 years. Neuro-protection looks the question that may be answered first. Knowing the loss of your axons and neurons has stopped would be fantastic. Having treatment which offered some repair (1 or 2 EDSS points) would be the icing on the cake. Q – am I asking too much (say by 2022)?
I’m not sure what to make of your list Prof G, especially in light of your less than optimistic views on myelin restoration in MSers.Franklin et al have been on a major PR crusade over the last 24 months in an attempt to generate funding for its impending trials for RXR-gamma treatments. Although an adequate treatment is some ways off, Franklin and the MS Society have been seeking donations of £150for the ‘Hope’ campaign which aims to introduce remyelination treatments by the end of this decade (even my parents donated £500). Furthermore, Franklin is on BBC and Sky News almost every other month elucidating on how revolutionary the progress is in the lab, and how he is very hopeful remyelination will be a tangible prospect in the very near future.Are we missing something here? Your list is more of a downer than reassuring.
Re: "Your list is more of a downer than reassuring."My title states 2012, which is why I played down remyelination. I am not aware of any human RXR-gamma trials starting this year. The news on the block is that human biology in relation to RXR-gamma and remyelination is not quite the same as the rodent. We need to wait and see how the human science pans out. What is happening in relation to remyelination is that big Pharma have stepped up to the plate and are batting first. Biogen-Idec are about to start a phase 2 anti-lingo optic neuritis remyelination trial. This is exciting, but will only deliver results by late 2014. The important observation about this trial is that they are doing it in early relapsing disease; obviously an easier target than progressive disease.
Re: "Neuro-protection looks the question that may be answered first."This has to be answered first it is the most pressing problem. For remyelination strategies to work you need to keep the axon alive long enough for it to be remyelinated. Once there is neuronal and/or axonal loss; the target for remyelination is gone.
Do the RXR-gamma drugs work as well on human cells and can such drugs repair old or scarred lesions?
"Do the RXR-gamma drugs work as well on human cells and can such drugs repair old or scarred lesions?These are very relevant questions and I do not think we know the answers, and this would essential information required BEFORE trials are undertaken.RXR is a widely expressed molecule and so the side-effect potential could limit the use of the drugs long-term in humans. Could we use in short bursts to drive repair? Human cells do not behave the same way as rodent cells, otherwise we would already have a source of human cells as the technology to produce rodent cells is robust.If human cells do not use this pathway to differentiate then thisso called "breakthrough" is hype and will be a bust.Can long standing gliotic lesions be repaired. This has not been shown as far as I am aware. To datedrugs have been reported to repair recent damage in rodents Therefore the trial design to target these different scenarios would be different.Perhaps we should ask Prof Franklinstein for comment.
Prof G,The UK MS society are funding a neuro-protection trail. Does it hold promise?Neuroprotective strategies: Amiloride Clinical Trial in Optic Neuritis (ACTION) Dr Matthew CranerUniversity of Oxford£377,283 What’s the project about? The aim of this project is to investigate the effect of amiloride as a new therapy for protecting nerves from damage following inflammation. Amiloride is a drug already used to treat heart failure and high blood pressure, so we know it's safe. The study will use imaging techniques to look at the effect of amiloride on nerve fibre loss in the retina of people following optic neuritis. How will it help people with MS? Effective therapies for protecting nerve fibres from damage in MS are urgently needed. It is also important to find ways of quickly assessing these therapies. This project could develop amiloride as a neuroprotective therapy for MS. The findings of this project will also pave the way for more clinical trials in the future. The difference you can makeProjects like this are vital if we are to achieve our goal of developing and testing neuroprotective therapies that prevent and slow disability progression.
Yes we know about the trial.It is using a trial design that we already pioneering with a differnt drug.Amiloride is an acid sensing ion channel (Potassissium and sodium channel) blocker. The idea is that too much sodium is entering the cells and causing them to overload and become damaged.The pre-clinical animal data looked pretty good and suggests it may be useful in treating progressive MS.
Re: "Neuroprotective strategies: Amiloride Clinical Trial in Optic Neuritis (ACTION)"This study is targeting acute optic neuritis and not progressive MS. I does hold promise and like any other putative neuroprotective drug needs to be tested in clinical trials.It is great news that the MS Society are funding this trial; another first for UK MS Researchers.
Re: "Neuroprotective strategies: Amiloride Clinical Trial in Optic Neuritis (ACTION)"This study is targeting acute optic neuritis and not progressive MS. I does hold promise and like any other putative neuroprotective drug needs to be tested in clinical trials.It is great news that the MS Society are funding this trial; another first for UK MS Researchers.