Remyelination. Is this war amongst scientists?

R

Remyelination is a hot topic

In the paper below they say

The view that differentiation of OPC into mature myelinating oligodendrocytes is required for successful remyelination in humans has been challenged recently. Measuring the integration of 14C derived from nuclear testing into DNA of oligodendroglial lineage cells Yeung et al. suggest that pre-existing oligodendrocytes and not proliferating OPC may contribute to remyelination in MS. Moreover, Jäkel et al. performed scRNA-seq analysis and identified different subpopulations of OPC and oligodendrocytes in brain tissue samples from MS patients and healthy individuals which only partly overlapped with oligodendroglial subsets identified in mouse brains. They propose that the loss of certain subpopulations and the skewing of the differentiation program to other subclasses of mature oligodendrocytes contribute to impaired remyelination in MS.

So the view was to para-phrase that the mousers have been wasting their time, but their (the mousers) response to this was to suggest that pathologists are essentially “useless”, and the tissues (shadow plaques) analysed in the above studies were not remyelination. The response by the pathologists has so far been non existent and suggests that they don’t mind being called “useless”. I have been frankly shocked by the responses to these questions by some people (pathologists) . This is a essential aspect of MS pathology. We need consensus

Lesion stage-dependent causes for impaired remyelination in MS.Heß K, Starost L, Kieran NW, Thomas C, Vincenten MCJ, Antel J, Martino G, Huitinga I, Healy L, Kuhlmann T.Acta Neuropathol. 2020 Jul 24. doi: 10.1007/s00401-020-02189-9

Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.

There is a lot in this and I am glad we (MDs) have not put too much energy into experimental remyelination studies, but a lot of effort and resource has. I am sitting on the side-lines watching this unfold, thinking surely the questions posed here are so fundemental that we need answers

The conclusions of this current study are disappointing

They say “pharmacological approaches that focus exclusively on promotion of oligodendroglial differentiation to enhance remyelination might fail“, treatment strategies targeting multiple of the steps required for successful remyelination, namely oligodendroglial proliferation, migration, differentiation, myelin sheath formation, and survival should be considered. Our data also suggest that promotion of remyelination in progressive MS in which mixed and inactive lesions dominate may require different treatment approaches compared to RRMS characterized by more active lesions.

This is not what you want to hear and trials have been planned on the idea of a maturation failure of OPC…Should they be put on hold?.

The Mousrs/Ratters need to respond to this one.

The MS Societies better get the pathologists together to get some consensus PDQ (pretty dammed quick) because if this can’t be done then we will start to say we can’t believe anything that these people are saying and have said in the past.

Having seen two present the opposite story with 5 minutes of each other and neither questions the other quite recently says either they don’t believe their own work or are frightened of the confrontation, but they have critized animal studies when it suites them and and used the same models subsequently, makes me concerned.

Surely there is no point in making new models unless you can agree what to model. As for new models, essentially none of the current models examine anything, but a acute demyelinating event that repairs without doing anything. Then we use that to justify a study where we think chronic demyelination with gliosis is present. If the study doesn’t work we blame the animal models rather than the scientists for not doing a translatable experiment.

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17 comments

  • That’s the missing link every pwMS is hoping to achieve!
    How about the approach with intermittent fasting which may lead to the creation of new oligodendrocytes ?
    “Autophagy Promotes Oligodendrocyte Survival and Function following Dysmyelination in a Long-Lived Myelin Mutant” (journal of neuroscience)

  • The Mouse 🐁 Roars! 😎👍🏼
    I don’t care who is right or wrong.
    I can’t understand any of these physiological changes except my Experiences.
    Thinking 🤔
    Sore on nerve fiber, then erodes, leaves bare wires, short circuiting or dead line.
    Doctors Please Do something about this!
    No Turf Wars Please!
    I appreciate Mouse Doctors and their dedicated mice subjects.
    Thank you for your honesty. You are Humans after all 🐭

  • Brilliant critique MD, and much appreciated, especially in the way you effectively deconstruct the respective arguments to highlight the stalemate. Is this a case of pathologists publishing to their own audiences in their own favourite journals so taking the easy route, and the mousers likewise doing the same to their own audiences and in their favourite journals? If so, this is where some clever clogs needs to come along and tie it all together, solve the problem and steal the glory. Good on them, bring it on. I remain optimistic – not from the current state but from the future if this kind of message gets taken on board. Great replies from Pedro and Mary.

  • Surely Cambridge et al haven’t been wandering down a blind alley for decades? 🙁
    Very worrying, considering the resource being piled into this. Definitely needs some sort of investigation asap before potentially more money is potentially wasted in these now desperately straitened times for research,

    • Welsh Mouse,

      I have to agree with you about the scale of funding into remyelination.

      I have a bigger issue with the overall impact of the research funding by the U.K. MS Society. They say on their website that they have spent £220 million on MS research since 1956. Nearly a quarter of a £ billion, yet I couldn’t name a single breakthrough research finding or point to a therapy which is available. A poor return after 64 years. And they are now seeking another £100 million for another vanity project (promises the Earth) which I doubt will deliver.

      The MS Society Cambridge Centre for Myelin Repair was established in 2005 and was given another £1.6 million (I believe last year). The Bexarotene trial which took a potential therapy identified from the Centre, cost £250,000 and was supposed to report results in September 2019 (can’t blame Covid 19 for the delay), but all has gone silent.

      I am 100 per cent a cynic. As a non-scientist / researcher I can’t understand why the primary aim of any research isn’t to understand the problem first – in MS what’s causing it and what’s driving it. And then develop possible solutions. The approach which seems to have been taken is: (1) a presumption that MS is a disease where myelin is lost leading to nerve loss and (2) a solution that is based on finding drugs to encourage myelin repair. I don’t think (1) has been proven beyond reasonable doubt. So (2) is a bit hit and hope. My own view is that (1) you can’t remyelinate lost nerves and (2) remyelination therapies are useless if the processes which cause the damage aren’t fully understood and addressed.

      Don’t even get me started on the MS Tissue Bank established in 1998!

      • Looks like we have a rare meeting of minds here, Sid. Must be some sort of planetary alignment I’m unaware of 😉
        Another question i’ve always asked but never had answered is, why haven’t the remyelination groups gone anywhere near inflammatory disease rather than just chemical-induced, often focal demyelination? I think I may know the answer…………………….

  • Remyelination trials:

    I see that Cambridge will now be reporting the results of the Bexarotene trial in September 2020. They are also planning a trial of Metformin and Clemastine to start this year.

    https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwjs1eTuu-_qAhUpVBUIHaG0DKkQFjAAegQIBBAB&url=https%3A%2F%2Fwww-neurosciences.medschl.cam.ac.uk%2Fjones-coles-group%2Ftrials-in-cambridge%2F&usg=AOvVaw0KgEOhzIZtUzRiNCUWkQKX

    On the plus side, at least these trials are in humans and the results should inform the debate as to whether remyelination is a strategy that is worth pursuing.

    • debate as to whether remyelination is a strategy that is worth pursuing……It depends on the trial design, if it is incapable of showing a difference it does not make a difference what you use.

      However if the idea of metformin is based on quick sand it won’t make a difference and as the plan is to use clemastine one suspects the bexarotene is a dodo…we’ll see and the MS Society may be funding more metformin trials

      • “MS Society may be funding more metformin trials”. Is it time to give those who design MS trials to take the i am stable genius test Donald Trump took? With over 1 in 3 with diabetes World wide. You’d think the data is already out there given ms people like normal people have the same chances of acquiring diabetes? Ms Society and some research clinics are driven by spending money to keep their budgets in tact. With poor science if need be.

          • Yes. OK. My point those with MS who have diabetes should have lower Edss and less severe relapses. Is this the experience at bars clinic? If not the isn’t it waste of money and more importantly getting ms peoples hopes for 10 years and then a dud like anti lingo!

    • ANONYMOUS
      August 1, 2020 at 7:35 pm Edit
      Yes. OK. My point those with MS who have diabetes should have lower Edss and less severe relapses. Is this the experience at bars clinic? If not the isn’t it waste of money and more importantly getting ms peoples hopes for 10 years and then a dud like anti lingo!

      Yes a very good point…and I suspect you are right, I could say more on this but I won’t at this time

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