Tuesday, 10 May 2016

Fingolimod (FTY720) may be neuroprotective

Experimental Neurology Vol 279, May 2016, P243-260

The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration

Sofia Anastasiadou, Bernd Knöl

Abstract

Fingolimod (FTY720) is a new generation oral treatment for multiple sclerosis (MS). So far, FTY720 was mainly considered to target trafficking of immune cells but not brain cells such as neurons. Herein, we analyzed FTY720's potential to directly alter neuronal function. In CNS neurons, we identified a FTY720 governed gene expression response. FTY720 upregulated immediate early genes (IEGs) encoding for neuronal activity associated transcription factors such as c-Fos, FosB, Egr1 and Egr2 and induced actin cytoskeleton associated genes (actin isoforms, tropomyosin, calponin). Stimulation of primary neurons with FTY720 enhanced neurite growth and altered growth cone morphology. In accordance, FTY720 enhanced axon regeneration in mice upon facial nerve axotomy. We identified components of a FTY720 engaged signaling cascade including S1P receptors, G12/13 G-proteins, RhoA-GTPases and the transcription factors SRF/MRTF.

In summary, we uncovered a broader cellular and therapeutic operation mode of FTY720, suggesting beneficial FTY720 effects also on CNS neurons during MS therapy and for treatment of other neurodegenerative diseases requiring neuroprotective and neurorestorative processes.

 Figure 1: (A) Outline of the facial nerve lesion model with the facial nerve represented as a solid blue line (at the start), dashed line (degenerating after its cut/axotomy) and red line (after injection of the Flurogold [FG] tracer 15 days following cutting). The facial nucleus (the start of the facial nerve in the brainstem) is stained with anti-FG antibodies to visualize the FG tracer. Fingolimod enhanced the number of FG positive motoneurones on the lesioned side (E) compared to sham/DMSO injected animals (D).

What happens when two different roads do not lead to the same place? We see this often in science, where one promising breakthrough is quickly disapproved by the turn of an article in the very same journal. Fingolimod (FTY720) has ridden a rocky road in terms of demonstrating its potential for remyelination (see http://multiple-sclerosis-research.blogspot.com/2015/07/novartis-maybe-now-believes-biogen.htmlhttp://multiple-sclerosis-research.blogspot.com/2011/07/fingolimod-does-not-promote.html). But is it right to ignore new information because it disagrees with the desired results?

Here, the authors provide more basic science evidence supporting a role for fingolimod in nerve repair, specifically neuronal repair. They demonstrate that fingolimod induces expression of neuronal plasticity associated genes c-Fos, c-FosB, Bdnf, Egr1 and Egr2, as well as genes encoding components of the actin cytoskeleton that make up axons. They also provide in vitro evidence that fingolimod stimulates growth cone filopodia extension in primary neurones (i.e. demonstrating a potential for initiating axonal growth in the CNS) and in vivo evidence that it enhances axonal regeneration of an injured facial nerve (peripheral nerve, see Figure 1). So there may be additional beneficial effects to fingolimod than simply sequestration of auto-reactive immune cells in lymph nodes. But like most findings in science, I don't think contradictory findings in science are senseless in themselves, but a necessary paradox.

“That was excellently observed’, say I, when I read a passage in an author, where his opinion agrees with mine. When we differ, there I pronounce him to be mistaken.” - Jonathan Swift (1167-1745).

22 comments:

  1. Why do you think that FIngolimod was such a miserable failure in progressive MS trial in humans (not animals) that was aborted by Biogen? If it is in fact stimulating neuronal gene expression, axon growth and regeneration, which is what you want in progressive patients, why do human trials fail?

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    1. Because the trials are rubbish? I have no I I put on this but this is a real question. ?

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    2. It is well known that the astrogliotic scar in MS injury contains inhibitors to axonal growth and repair such as CSPGs. I doubt that the facial nerve lesion model mimics the gliosis and inhibitory environment of MS.

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  2. lol. If Gilenya did initiate axonal growth or remyelination, how long would it take to notice these effects? wouldn't someone notice a trend with disappearing lesions?

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    1. in the facebook group of Gilenya users, several have reported fewer or smaller lesions in their MRIs after a time on G. I myself had symptoms that had not cleared up within a year while on Copaxone but they did clear in the following 2 years on G (by now, I am 4.5 years on it). The latter is not necessarily a sign of remyelination helped by G, but it could be.

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    2. I am also I was wondering the same thing about the failure of Fingolimod in PPMS.
      In my last visit I saw my neuro attending a man of 27 years old that the neuro redefined as having SPMS. It's in Fingo for almost 06 months. For the analysis of neuro he had clear interruption of accelerated brain atrophy he was presenting, he has black holes injury.
      I know it's a case report isolated but I see the same reports in forums on Facebook about Fingolimod ...
      Maybe Fingolimod can undergo a new trial for MS Progressive.
      I don't know, maybe Fingolimod with Copaxone, or Fingolimod with another Neuroprotective drug...

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    3. AnonymousTuesday, May 10, 2016 12:53:00 pm - according to one of the contributors to this blog, "up to 30% of lesions have been reported to disappear on follow-up", whether from natural remylienation that takes place in the early stages of RRMS or from inexact MRI images. I think there have also been reports of disappearing or decreasing lesions in the context of tysabri, lemtrada and hsct. if gilenya is promoting remyelination then surely we would need to see more reports of disappearing lesions than we're normally used to?

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    4. The theory of Professor Vollmer may gives a remarkable answer. Cinara! I suggest to watch it!
      https://www.youtube.com/watch?v=WOYI8_5JZUY

      He told the same: MS mainly a subclinical inflamation which caused brain atrophy. Youg patients is often diagnosed SPMS, so they do not got the highly effective drugs, which not only prevent relapses, but also reduces subclinical inflammation too. Without this inflammation the brain got a chance to regenerate itself. Moderate daily excercise younger age, helathy diet with highly effective drug resulted significant improvement.
      He think the older age and magnitude of brain volume leads SPMS (brain cannot regenerate itself, and - after long years - mask damages)

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    5. Thanks for sharing anon, very interesting.

      However it doesn't explain in my mind why tysabri and lemtrada failed in progressive trials? Surely by dampening down inflammation, we should have seen a reduced rate of progression?

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    6. Lemtrada progressive studies were look-see experiments not a proper trial

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    7. Wow thank you Anon 17:08, I din't know the theory of the Prof. Vollmer.

      I realized that my neuro was out of options to treat it and decided to take a risk and leave the boy with fingolimod, and really there was improvement in exam results by MRI.

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    8. Younger age means younger brain which means more plasticity, and reserve, and may can mask permanent damage.
      Not only flares leads the progression if you have RRMS, but also the brain atrophy, which growing continously from the begining to the advanced stages. So very-very important to choose DMD which has effect on brain atrophy!
      Hit hard early and effectively!

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  3. These results may suggest it
    https://actrims.confex.com/actrims/2016/meetingapp.cgi/Paper/1484

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  4. Does this suggest Fingolimod in combination with another DMT???

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  5. Combination of Fingo plus another DMT would increase risks of interest tions etc

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    1. infections and side effects etc? lol. i love predictive text, it keeps us all sharp ;)

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  6. It is important to consider trial patient composition in the INFORMS (fingolimod in PPMS) study. Approx 40% were over 50 and 85 percent wirhout Gd enhancement on MRI. Now compare this with most RRMS trials, the drug had no chance. I have always thought that PPMS was a harder sell than SPMS. Let's see how Siponimod (second generation fingo) does in SPMS!

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    1. lol. i thought gilenya patent was about to expire, haven't heard about siponimod til now though i see the trial dates back to 2013

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    2. If siponimod works in SPMS and fingo dint work in PPMS then the trial design is wrong as the drugs are essentially the same bar activity on a couple of S1P receptors. However lets wait and see, the results should be soon

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    3. Agreed, F Lublins assertions that it was not the trial design needs to be re-evaluated. Having said this narrowing inclusion criteria only restricts recruitment!

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  7. Combination of Fingo plus another DMT would increase risks of interest tions etc

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  8. Speaking of class S1P inhibitors have any ongoing research looking to
    blockers S1P2 and/or S1P5?

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