Thursday, 26 March 2015

Neuroprotection and regeneration is this the new way forward

Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection inMultiple Sclerosis.
Demicheva E, Cui YF, Bardwell P, Barghorn S, Kron M, Meyer AH, Schmidt M, Gerlach B, Leddy M, Barlow E, O'Connor E, Choi CH, Huang L, Veldman GM, Rus H, Shabanzadeh AP, Tassew NG, Monnier PP, Müller T, Calabresi PA, Schoemaker H, Mueller BK. Cell Rep. 2015  pii: S2211-1247(15)00206-5. doi: 10.1016/j.celrep.2015.02.048. [Epub ahead of print]

Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. In vitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibres, accelerated functional recovery, and protected the retinal nerve fibre layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients.




Repulsive Guidance Molecules (RGMs) are members of a three gene family (in vertebrates) composed of RGMa, RGMb, and RGMc (also called hemojuvelin). RGMa has been implicated to play an important role in the developing brain and in the scar tissue that forms after a brain injury. For example, RGMa helps guide Retinal Ganglion Cell(RGC) axons to the midbrain. It has also been demonstrated that after induced spinal cord injury RGMa accumulates in the scar tissue around the lesion. Further research has shown that RGMa is an inhibitor of axonal outgrowth. Taken together, these findings highlight the importance of RGMa in axonal guidance and outgrowth. In this study they made a blocker of RGMa and this facilitated recovery and may have stimulated nerve outgrowth.  It is open source so you can all read the paper.It will have the same problem as the anti-Lingo in that it has to get into the CNS (Biogen claim that it is the 0.1% that gets in that does the business.) However very encouraging

Dear Company, if you are reading this and you want to put this to the test contact us!.

CoI This study was performed by a pharmaceutical company so it means they have the potential to develop this molecule.

43 comments:

  1. Agree with MD we'd love to get our hands on this and try it in our model.

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    1. Why don't you contact the corresponding author(s) of this paper?

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    2. I'll wait until ProfG gets back from his travels so he has the right contact

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  2. This look exciting. Is this the big news that you were promising progressive MSers

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    1. No but it indicates that despite perception there is now an accelerating pace of research into treatments for progression.
      Big news to follow ;-)

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    2. I think one can deduce what the big news is from the slides but well I will let myself be surprised!.

      However, you should state in the study mentioned above that it is probably years away from pills being made - the big problem is that we don't have much time - I wish the pharma would hurry up otherwise it's too late for all of us here.

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    3. MD2 "Big news to follow".

      I thought I'd asked Big Mouse to keep you on a tight leash. You are like an over-excited child. I am off on holiday for two weeks and return on 13 April. When I log on to this blog on 14 April, will I see the big news posted? As you are about to explode (too many beans) why don't you do us a favour and tell us what it is - it will be good for your soul. You might upset a few fellow researchers, but you have to break a few eggs to make an omelette. Confession is good for the soul MD2. Time for you to let us know the news.

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    4. No, he's just sworn to secrecy. Sorry, have a nice holiday!

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    5. Another day closer! Have a great holiday! ;-)

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    6. My holiday would be much better if you could spill the beans (just to me). I've tried to be nice, but now have to resort to threats. I will vote for the English Independence Party at the general election. This could mean valley boys like yourself heading back over the Severn and a wire fence being erected along Offa's Dike. I don't want it to come to that, but you are forcing my hand. I don't imagine there's much high quality research in Swansea! The choice is yours, either post the Big News by close of play next Wednesday, or face the prospect of a new career caring for abandoned pit ponies. Gffyyffgg gffggg llfgggy (that's Welsh for spill the beans).}

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    7. I'm not sure Nigel Farage (interestingly descended from a Huguenot immigrant) would send us Welsh back as we were here first! We ate all the pit ponies after Mrs T closed the mines.
      The Welsh for spill the beans is Gollwng y ffa ;-)

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    8. My holiday would be much better....something to look forward to on your return:-)

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  3. Ingenious & fascinating.

    Looking forward to the big news from you clever mice.

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  4. Well done Yahoo mouses

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  5. Well, isn't it funny that steroids which we know to be effective in relapses reduces this?

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    1. Could this be the reason why huge doses of steroids are needed in relapses? Apparently, much lower doses shuld be sufficient to reduce imflammation

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    2. Steroids are the panacea of neurological disorders, even in disorders with little documented inflammation, but used by neurologists because it simply works. There was a clever piece of work done by a researcher called Massaro who measured CSF neural cell adhesion molecule (a molecule responsible for growth axons) in MSers given steroids after a relapse. In serial LP's he showed that this molecule significantly rose only in those given steroids!

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  6. Has anyone seen the movie "Rise of the Planet of the Apes"? It sounds like neurogenesis. Can the mice talk as well as be less resistant to EAE?

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  7. When are the phenytoin results due out? They should have been published a month ago.
    Yet another sodium channel drug, along with many others being trailed at the moment for neuro-protection.
    However, this one may have given better results.

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    1. phenytonin is one of the worse soium channel blockers we have tried

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  8. From the paper: "Moreover, activated microglial cells express RGMa on their surface, and its downregulation by minocycline results in enhanced axonal growth both in vitro and in vivo". What is the current status of minocycline in MS?

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  9. I dont know. in rrms I would predict not much. The animal data had severe problems it was given into the peritoneum but the problem is if it is not Ph balanced it is like giving sulphuric acid and I suspect much of the effect was due to a stress response. We had a look at it amd we could show a neuroprotective effect. It was just that sodium channel blockers like oxcarbazepine were much better. So you really should sign up for PROXIMUS. p.s im conflicted here

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  10. Biotin might kick all this in the balls and actually be affective in stopping progression by the grace of god.

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  11. I think everyone's got their fingers crossed on biotin

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  12. Mouses? I know your not going to want to spill the beans yet but can you at least tell everyone if the news for progressive Ms is news as in a treatment?

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  13. What day are we expecting news? Based on your enthusiasm this must be a seriously big announcement? I.e treatment?

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    1. MD2 is being a bad lad..or lass and teasing me. If you are building things up, get ready for a fall.

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    2. What day for news no idea....you get the news as it arrives every day.

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    3. I doubt that's a ready treatment cos that needs to take years - it's more likely a really good trial result - something that caused a complete stop of progression in ALL trial participants - RRMS as well as the progressives.

      So a real game changer - something really useful to track back to the source of the disease.

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    4. MD2 is a Welsh guy called Gareth (my condolences on both counts). Both MD1 and 2 graduated with distinction from the University Marquis de Sade. Cruelty is their middle names. Killing mice is their day job. What they have inflicted on us is cruel. It's the hope that kills me! I suspect the forthcoming news will not be earth-shattering. Whatever research / trial results are published we can be sure of "more research required", "results need to be replicated", "biiger trials needed". The usual cut and paste used by every MS researcher. In their former lives these mouse doctors were Japanese soldiers overseeing the construction of the Burma railway in WW2. Richard III is a saint compared to the Mouse Doctors. This last week has left me drained. Chinese water torture is a process in which water is slowly dripped onto a person's forehead, allegedly driving the restrained victim insane. These guys are black belts in this process. You build us up to knock us down. The good news will not be that good - MD2 has over-egged the situation. My payback - I will never nominate these mice for MS Society researcher of the year, i will pay the tooth fairy to cut off MD's pony tail, I will never again buy a CD of Tom Jones, Charlotte Church or Shirley Bassey (watch the Welsh economy collapse MD2). When you go to your beds tonight and sleep soundly after a night at the pub, think of people like me, laying awake waiting for the good news that never arrives. I hear they are to make a new Chitty Chitty Bang Bang film. Both of you could step into the role of the childcatcher with ease. I thought you guys were nice - what a fool I have been.

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    5. I will put you out of your misery...any news in the near future is not going to be Earth Shattering.

      Chity Chitty bang bang was written by Ian Fleming who created James Bond and we are indeed licensed to kill...but you have to stop beating yourself up;-). As I have said many,times this week the only good news that may satisfy the bloggers is if something comes through phase III and shows efficacy. Then we have to hope that pharma is there to develop it.

      If there is big news, pharma have to tell their share holder first so as we have not heard this yet....the only big news is if there is a private company with no shareholders but I can assure you that we have no idea what MedDay is up to....Lets hope that Biotin is great.

      As to Researcher of the Year you seem to be dashing our hopes of meeting JLS...I'm gutted:-(.

      PS Im off to build my bridge over the River Kwai

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  14. So Mouses? Can we have the news? You've got everyone's hopes up just spill the beans! Especially after your setting yourself up for a fall comment, every day for people with Ms is a day too long to hear good news

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    1. No.....there are no beans for us to spill as we have consistently said .

      Isn't this story good news?

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  15. In which case you need to tell md2 to sort his attitude out he is raising the hopes of people with a desperate disease and this is not something to play with, I appreciate the blog is good for all to keep informed and it's great that you do it, but you need to realise that teasing and baiting people is not on full stop

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    1. I suspect he/she can read ...I'm off to take a chill pill

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  16. The take a chill pill comment has been said before, you know yourself that false hopes and game playing is out of order

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    1. As the master of games,,,how do I respond.
      One day closer.?

      We get good and bad news in advance of prime time, some snippets may leak the news may be good to us the news may be bad we may even think the good news is not that great but we can not say anything. We have to wait until it goes in the public domain. Once in the public domain then we can post....stop prodding and you won't feel any bait

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  17. Understandable but it's the implication of the suggestion that it's great news for progressive disease
    All hope that it is near treatment

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    1. It is all relative...what is good news for us is necessarily the not the same as good news to you.

      If fact great news may be terrible news. What do I mean by that. Simvastatin for example it is great news that it appears to slow down progression as shown in the phase II that gives us hope that we have a trial design to show an effect of an agent. Great news to us however,the fact that there is no patent protecting the idea and costs £2.70/week and therefore pharma have shown no interest so far, means that this information is probably meaningless as far as delivering a treatment to you, So it is surely not great news.

      So do we do a phase III trial one step closer to getting a drug to you. But they will have to answer not only does it work but is their a dose response as there is no need to take 80mg if you can take 20mg and reduce side effects. This should be needed to satisfy the regulators. This adds hundreds of people and a lot of cost. It works great news for us, maybe bad news for you, because with no pharma interest then what?.....it still has to be approved and we will not have done two trials. Bad news to us is that the trial will cost so much money no body besides pharma can afford to do this.

      OK point taken we will have to watch our words...but if you want us to make comments you have to accept that there will be times we will get it wrong and times you wont like what we say. Just as we accept there are times when one of you says something we really don't like.

      You point has been made are point has been made...the comments have nothing to do with the post and thats it thanks

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  18. Am I not correct in thinkn there's gnbac1 md1003 and your charcot that all look promising

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