Remyelination therapy is going to be a bust?

R

We need a bit of a Swedish Civil war before we review this one. Why? One Swedish group argues that when oligodendrocyte repair they do so from existing oligodendrocytes, but the work of ratters and mousers and this Swedish group argue that they come from oligodendrocyte precursor cells. If the former view is true then this paper could be worthless. The ratters have laid down the challenge that the tissue on which the first Swedish study was done was duff and in part have had a go at the pathologists.

The pathologists I am sorry to say have run a mile when asked to challenge/address this view. I have seen some of the correspondence from some very senior pathologists and it woeful. This question is one of the most important question that needs addressing. Can experiments be done to disprove the arguements of the two different camps.

This study suggests that they have found a switch factor that allows oligodendrocytes to mature and produce myelin.

A lovely piece of work and the hard work of a student, Karl Carlström.

They say that a protein called GSTA4 is upregulatated and can prevent cell death of oligodendrocytes, so if you do the studies in animals with extra GSTA4 they remyelinate better and get less severe EAE.

Hoorah we say.

However you don’t care about the hard work and whether this is how oligododendrocytes mature, what you want to know is whether this is going to give you a remyelination treatment.

When we look at the last sentence of the abstract and it says “a potential target for future reparative MS therapies“. This gets you and the media excited and it is the next “cure of the week”.

Hooray we say

But on this blog, we learn together. I have to do some reading when news comes out. I have to try an understand it and then I have to think does it create a treatment target. I am sorry to say “Don’t hold your breathe.

Where is it? It’s all over the place. As with all the oligodendroctye rejuvenators reported so far, the targets are expressed all over the place.

Therefore if you have a drug against a target that is all over the place, one worry is side-effects.

Data Chart Image
GSTA4 expression at http://www.biogps.org
So you can see in blue it is all over the nerves. Lets do back to Sweden (below) to the oligodendrocyte gene expression site and surprsing not much on the oligodendrocyte in mice or humans or in MS and not much on oligodendrocyte precursors or myelinating oligodendrocytes e.g. those that make MOG

In this study they say that GSTA4 was low and when it appears it helps oligodendrocyte precursors turn into myelinating cells. Whilst this may not be evident in oligodendrocyte development websites https://ki.se/en/mbb/oligointernode. You can see it is low in oligodendrocytes and precursors

olig2 is a presursor marker
MOG is on myelin

However, now my concern.

They come to this pathway because it is upregulated by Dimethyl fumarate. This study therefore implies dimethyl fumarate is a remyelination agent. They spent the early life of dimethyl fumarate claiming it was neuroprotectiive too.

If this is true and it is a remyelinating agent, we have to ask. “Does it make you do better when you take dimethyl fumarate, does it reverse the ravages of MS?”.

Evidence for the effectiveness of dimethyl fumarate has come from two large clinical trials.

  • DEFINE – Tecfidera compared to placebo (2012)

This two year study compared Tecfidera taken either two or three times daily and placebo in more than 1,200 participants with relapsing remitting MS. Compared to placebo, Tecfidera twice daily reduced the number of relapses in one year by 53%. Tecfidera twice daily reduced the risk of 3 month disability progression by 38%.

  • CONFIRM – Tecfidera or Copaxone compared to placebo (2012)

This two year study with 1,232 participants was similar to DEFINE, but with an additional group who took Copaxone (glatiramer acetate) for comparison.

Tecfidera reduced the number of relapses in one year by 44% for the twice-daily dose compared to placebo. In contrast, Copaxone reduced the number of relapses by 29% compared to placebo. The reduction in disability progression observed in the DEFINE study was not seen in the CONFIRM study.

So if this is what a remyelination and anti-inflammatory agent shows, I say we have to be concerned for this approach, as it does not appear outstanding as we want a remyelination agents to be. You can’t have if both ways!!

Now there is a question mark about how well Dimethyl fumarate gets into the CNS and you have to remember the active chemical is monomethyl fumarate. Yes I am playing Devil’s advocate. But someone needs too before we get carried away.

Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis.Carlström KE, Zhu K, Ewing E, Krabbendam IE, Harris RA, Falcão AM, Jagodic M, Castelo-Branco G, Piehl F.Nat Commun. 2020 Aug 13;11(1):4071. doi: 10.1038/s41467-020-17871-5.

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.

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MouseDoctor

4 comments

  • So do you think that it might help any at all? I’m sorry, just trying to read through quickly because my kid is distracting me and I do want to pay attention to her lol.
    I remember reading not too long ago that you or someone else found that clemastine likely reduced brain volume or had negative effects on cognitive function? I had actually been taking that but stopped. My neurologist didn’t care either way. She said that while she was doubtful that it would help, it wouldn’t hurt. Basically take it if ya want to, even if it doesn’t help it’s harmless. But I definitely don’t want to take anything that will have negative cognitive effects or accelerate loss of brain volume.
    Would the medication discussed cause that too? Sorry if this is jumbled up. I’ve probably already lost a lot of mental sharpness 🤦🏻‍♀️
    Thank you for doing so much investigation into so many things and sharing this information. You’re very appreciated.

  • I’m sorry if this comment isn’t put together well. I’m distracted because I’m trying to talk to my daughter about a movie that she likes while reading that and typing this lol. I obviously don’t want her to feel ignored lol.
    I remember reading something that you or someone else wrote saying that clemastine probably has negative effects on brain volume or cognitive function. I’d been taking it, but stopped after reading that because I definitely don’t want to take anything that would worsen or accelerate the worsening of either.
    I had a brief discussion with my neurologist about it about a year ago before taking it. She was doubtful that it would help but said that it was harmless to take. Her opinion was basically neutral, just said you can take it if you want to because it won’t hurt, but I don’t really expect it to help.
    Anyway, after reading the post above I don’t think it’s specifically about clemastine, but a different drug being researched. Do you think that the medication discussed above could cause or accelerate worsening of MS problems? I’m sorry for this distracted comment and question. I will read it more carefully tonight.
    I want so much for something to help reverse demyelination, even if it only helps a little bit. I really wish that there was a medication in the works that really helped to do that. I wouldn’t even care that much about side effects as long as they didn’t make the effects of MS itself worse. I grasp at straws for that every day 🤦🏻‍♀️
    -off topic but connected a bit at the end- Like my neurologist now classifies me as having failed Ocrevus due to having a relapse after 3 doses and is encouraging me to consider Lemtrada. Maybe my cognitive function is already worse than I thought it was, but the idea of taking that in spite of its safety profile just to lessen the probability of relapses concerns me a lot. So I’ve spent the last week weighing the possible pros versus cons, trying to decide if it’s worth it to take the risk for just the possible benefit. This probably sounds ridiculous, but if I was considering a medication that had a decent chance of causing remyelination but had a slightly worse safety profile, I wouldn’t hesitate to take the risks. I’m comparing apples to bananas, I know.
    I, and quite a few others in physical conditions similar to mine, are so desperate for something that might help. It’s pretty depressing to think that we won’t ever see a treatment that has a chance of repairing existing damage 😕.
    Anyway, thank you for doing so much research and for sharing it with the public. Your work is very appreciated!

    • “I remember reading something that you or someone else wrote saying that clemastine probably has negative effects on brain volume or cognitive function”….Not me. Maybe it was ProfG when he was talking about Cholinergic drugs.

      There is nothing here to suggest that clemastine would worsen anything. The point I was making is that DMF and clemastine increase GSTA4 but because we use DMF and it is not the best drug ever and does not make the disabled walk again, it potentially says that the target is not going to give us miraculous effects. This will counter the gushing you ave got elsewhere when others report this paper to say remyelination is round the corner using available MS drugs. My comment does not say that they don’t improve remyelination.

      Apples and bananas…It’s how you spin your story for example alemtuzumab improves disability. It was the case that the degree of disability reduced after alemtuzumab does alemtuzumab cause repair. That was the story spun Fox EJ et al. Alemtuzumab improves neurological functional systems in treatment-naive relapsing-remitting multiple sclerosis patients. J Neurol Sci. 2016 Apr 15;363:188-94. Lymphocytes make nerve growth factor an alternative view could be that if you get rid of inflammation early enough then it allows the natural repair mechanisms to do their job so the drug is not a cause of the repair. Therefore starting later may not give thee benefits.

      I am sure repair of the myelin can be achieved to some extent but this target is only one of many that have been reported, it may be possible to get an agent that is markedly more effective than DMF at inducing GSTA4. Likewise you may need to get the macrophages young. This is why studies with metformin are planned. I am not sure if COVID-19 has delayed things.

      If correct you may think that people with diabetes taking metformin would do better in COVID-19…I’ll look

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