Sunday, 30 July 2017

Tadpoles for MS drugs

Mannioui A, Vauzanges Q, Fini JB, Henriet E, Sekizar S, Azoyan L, Thomas JL, Pasquier DD, Giovannangeli C, Demeneix B, Lubetzki C, Zalc B. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.Mult Scler. 2017 Jul 1:1352458517721355. doi: 10.1177/1352458517721355. [Epub ahead of print]

BACKGROUND:

In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

OBJECTIVE:

A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

METHODS:

In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin (cell killing drug) . Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve.

RESULTS:

Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 (gene excising) gene editing showed that the pro-myelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5.

CONCLUSION:

This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known pro-myelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Whilst we have been hearing about monkey work and you know about the meecie stuff, but there is a movement to replace such animals with animals that are lower down the  chain of sentience. We recently heard about an EAE model in Zebra fish. They have transparent bodies and you can make their nerves or oligodendrocytes "glow in the dark" so you can watch things happening in real time.

So this study moves down the evolutionary ladder and moves us to amphibians. Xenopus is the African clawed toad, that many of you may have seen at school.   This study makes tadpoles with oligodendrocytes that glow in the dark and have been engineered so that they kill them in response to a drug. The default then is repair and remyelination.  So its abit like the chemical-induced demyelination in mice. 
In this study they test to see if drugs will make the myelin appear quicker.

In this study they report that that siponimod is one of the best agents to promote myelin. Is this good and bad news? 

The good news therefore is that here you have an agent that can block the immune response by modulating Sphingosine-1 phosphate one IS1P1) receptor and block relapsing EAE but as shown here it can promote remyelination, via an action on Sphingosine-1-phosphate five (S1P5) receptor. Siponimod has been shown to inhibit secondary progressive MS in phase II, so it could be round the corner from use. 
But the bad news is it does not appear to make miraculous recoveries, and so if this is remyelinating it warns that we have to be realistic of what remyelination therapies may offer. Furthermore remyelinating a nerve that will remyelinate any way may not be the same as trying to remyelinate chronic gliotic lesions.
Next question what is the difference between siponimod and fingolimod? Fingolimod targets S1P1 and S1P5 and also S1P3, and S1P4. there are many inferences that fingolimod was also remyelinatory, but there was contradictory evidence, but remember this agent failed in progressive MS. Was this because they didn't measure hand function?

You asked which compounds were screened
As you can see there is Biotin, Clemastine, Benztropine, fingolimod. At the top of the pile was Clemastine, albeit at a much higher doses than UC-42-WP04, then siponimod and then fingolimod, RXR and Bentropine. At the bottom of the pile was Lithium and MDL29951

9 comments:

  1. Where is the full paper, is that to come later? I can't find it.

    Which molecules did they screen, how large was the library and how was it chosen? Did they screen molecules that have already been found to be potent remyelinators like estradiol, testosterone, T3, micanazole, etc? It's really important to know this.

    I could see a use for siponimod as a maintenance therapy after Alemtuzumab or HSCT. Break the inflammation initially then make sure it never comes back with the addition of a helpful neuroprotective component. We know that using siponimod and fingolimod as first line therapies is probably pretty stupid because they (perhaps permanently) destroy the efficacy of more effective immunomodulators like Alemtuzumab.





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    1. http://journals.sagepub.com/doi/pdf/10.1177/1352458517721355

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    2. Thanks for the link. Weird stuff, I don't have access to multiple sclerosis journal unfortunately.

      Can you inform me on my main question which was about which molecules they screened and how the library was chosen? Do they reveal anything about that?

      Thanks.

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    3. Interesting, thanks for that. It's good they screened some molecules already known to be remyelinating. This screen, then, compounds the evidence that Clemastine is a potent remyelinator.

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  2. Is there any evidence that remyelination prevents neurodegeneration?

    How does siponimod slow down progression in SPMS? Is it through remyelination and hence slowing neurodegeneration? I have never understood how siponimod exerts its effect and yet fingolimod failed? It is probably not by blocking egression of lymphocytes from lymph nodes only. Siponimod must do something fingolimod doesn't.

    Why do remyelination trials take such a pathetically long time to complete? Shouldn't patients notice an abrupt change as do lab rats in remyelination trials?

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    1. More evidence for demyelination promotes degeneration

      How does siponimod slow progression...its an immunosuppressive.. Did fingolimod really fail or was it the trial design?

      Fingolimod has broader activity that siponimod

      Why do remyelination trials take long time to complete...not the right trial design.

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    2. Thanks for post and response MD. Siponimod has an effect of astrocytes and remyelination, whereas I cannot find this with fingolimod.

      J Neuroinflammation. 2016 Feb 8;13:31. doi: 10.1186/s12974-016-0494-x.
      The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures.

      O'Sullivan C1, Schubart A2, Mir AK2, Dev KK3.

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  3. Overally fingo near to natalizumab. Natalizumab an effective hand function preserver. My sister has posterior fossal Ms with atrophy, fingo significantly improves her hand function. She more faster then was before. Before G she progressed day by day, from the starts of G her MS much more calmer, and she experienced significant improvements in relation of her Qol and her MS remain stable 3-3,5. I hoe it can continue for long-long time.

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