It is not often that I get to watch the 6 O’clock News, but I had just got off a call with MS, as we are now closed for Christmas and so was surprised to see MS in the News.
Caroline is a reporter who is taking part in the MS-STAT2 trial which is been run by Sir Jeremy (You need to be a regular blog reader to know the story behind this). It also also featured Partick (below) who is one of our Expert MSers and is part of the BartsMS team. With lock down I haven’t seen him, except online a few weeks ago at a teching event, so it was pleasure surprise to see him on TV.
This report was about MS-STAT2 Multiple Sclerosis-Simvastatin Trial 2 (MS-STAT2)
Patients with a confirmed diagnosis of multiple sclerosis (MS) that have entered the secondary progressive stage. Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.
If you live in the UK and are eligible maybe consider signing up.
There are lots of sites across England Scotland, Northern Ireland and Wales The link is above…..If you want abit more science read-on.
This is a trial on statins. You may be surprised to know that MD & MD2 started off this all off in about the year 2000. You say “yeah right you started it off. What a pile of cobblers”. However you would be wrong. You may not know that MD2 is a blood brain barrier expert and many moons ago we were working at the Institute of Ophthalmology on blood brain barrier stuff.
It was evident that white blood cells push their way through blood vessel cells to get into the brain. To do this the blood vessels would talk to the white blood cells and they would have to reshape their skeleton to allow this to happen. Our mate, John Greenwood along with Pete Adamson had discovered the pathway that allowed this to happen. One of the important molecules involved in this was made from the cholesterol pathway. So John argued that Statins should inhibit this and so MD1 & MD2 did the experiments to show this.
We also knew that Prof Steinman (the Neurologist who had published in the Jouranl Nature probably more than anyone else in the MS field and had the same data as us as we saw it presented at a science meeting. However their mechanism of action was that the statins altered the cytokine balance…like every other treatment in those days. So we thought lets do a back to back submission to Nature. End result.
The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.Youssef S, Stüve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS.Nature. 2002;420(6911):78-84.
Yet another TH2 cells inhit EAE paper in a major science mag (Yarn).
These days nobody gives a stuff about TH2 cells and the mechanism of action would probaly follow dogma. No wonder we seem bitter and twisted.
Anyway what happened to us?
Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis.Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, Adamson P.FASEB J. 2003;17(8):905-7.
So as you can see the same old, same old was shoe-horned into Nature and out effort was dumped on the maggot pile, because “we did not prove our mechanism”. This would have needed us to make a knockout mouse that would not have survived. Surely the point is you can’t disprove your mechanism.
Prof Steinmann had done science three-ways in their paper. Like masterchef where the Michelin-starred chef, cooks vegatables in three differnt styles to show how good you are.
In “three-way science” you do the same experiment in three different ways and do loads of diagrams so no-one questions the results…which may show the effect is marginal. MD2 had done the experiment that showed the Th2 idea in Natutre was a load of old tosh. So what does it say about the reviewers.
Anyway, you allow the animals to develop disease and then you treat with a statin (red line) . When they are being treated there is no disease. Other animals get the dummy drug (blue line) . Virtually all animals develop disease. You stop the drug and you know that this takes about 2 days to clear and then guess what? Two days after you stop the drug, nearly all animals have a relapse. If the statins had converted cells into Th2 cells to stop disease then disease would not have developed because Th2 were not known to revert back to Th1/Th17 cells. Therefore Dogma was not correct.
Anyway MD & MD2 left the Eye Institute to go to the Brain Institute to work with ProfG and Prof Greenwod carried on the statin story. By the time we had got our work published, other groups had done trials in relapsing MS and they had failed. But Prof Greenwood teamed up with Sir Jeremy to do a trial and that was MS STAT and strangely it was done in secondary progressive MS and guess what? There seemed to be a slowing of loss of brain tissue.
Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS–STAT): a randomised, placebo-controlled, phase 2 trial.Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R.Lancet. 2014 Jun 28;383(9936):2213-21. doi: 10.1016/S0140-6736(13)62242-4.
So I have to say this does not make sense if the statins were inhibiting migration of white blood cells into the brain as it should have worked in relapsing MS. So how and why does the statin inhibit progressive MS?
- Inhibits Th2 T cell cytokines. Th2 cytokines have not had much of an impact on MS in trials and CD4 T cell depletion does not inhibit progressive MS
- Inhibits T cells getting in to the CNS. T cell depletion with alemtuzumab is not considered to inhibit progressive B disease so it it this?
- Inhibits B cells getting in the CNS…You say we can’t be bothered to waste our time with B cells However natalizumab did have some activity in progressive/advanced MS, if you did a trial lasing 3 years, had hand function
- The study tested the hypothesis that the reduction in cholesterol levels was the cause of the positive impact simvastatin had on brain atrophy and on disability . Results showed that simvastatin’s effect on clinical outcomes and brain atrophy were largely independent of cholesterol. But we had shown thown twenty year ago.
- The cholestrol pathway is involved in advanced MS. The chlosterol pathway is the most dysregulated pathway in progressive EAE, and alzhiemers disease so it has something to do with neurodegeneration.
- The cholestrol synthesis pathways create oxysterols that influence potassium channel activity that counter the excitotoxicty response of sodium and calcium and therefore inhibit neurodegeneration . Abit more plausible than 1-4.