Thursday, 28 November 2013

Blocking LINGO1 in fish promotes myelination

Yin W, Hu B Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish. Exp Neurol. 2013 Nov. doi:pii: S0014-4886(13)00336-1.10.1016/j.expneurol.2013.11.012. [Epub ahead of print]

Demyelinating diseases include multiple sclerosis, which is a neurodegenerative disease characterized by immune attacks on the central nervous system (CNS), resulting in myelin sheath damage and axonal loss. Leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitory protein (Nogo) receptor-interacting protein-1 (LINGO-1) has been identified as a negative regulator of oligodendrocytes differentiation. Targeted LINGO-1 inhibition promotes neuron survival, axon regeneration, oligodendrocyte differentiation, and remyelination in diverse animal models. Although studies in rodent models have extended our understanding of LINGO-1, its roles in neural development and myelination in zebrafish (Danio rerio) are not yet clear. In this study, we cloned the zebrafish homolog of the human LINGO-1 and found that lingo1b regulated myelination and oligodendrocyte differentiation. The expression of lingo1b started 1 (mRNA) and 2 (protein) days post-fertilization (dpf) in the CNS. Morpholino oligonucleotide knockdown of lingo1b resulted in developmental abnormalities, including less dark pigment, small eyes, and a curly spinal cord. The lack of lingo1b enhanced myelination and oligodendrocyte differentiation during embryogenesis. Furthermore, immunohistochemistry and movement analysis showed that lingo1b was involved in the axon development of primary motor neurons. These results suggested that Lingo1b protein functions as a negative regulator of myelination and oligodendrocyte differentiation during zebrafish development.
The Zebrafish has clear young and you can genetically manipulate the fish so you can see myelination happening. In this study they look at the effect of blocking LINGO1 and this caused more myelin to form and also helped nerves grow,so if it is important in myelin formation in fish and rodents, there is a good chance it is important in humans too. Pharma thinks so and there are studies to deliver a LINGO-1 blocking molecule. I only hope enough of it can get into the CNS to do its stuff.

9 comments:

  1. That's one cool looking fish........wonder what happens to fish that lose myelin? Do they drag there tail fin?:-) According to Biogen they just do IV infusion. Enough of the protein gets across.http://www.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/P02.021

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    1. No myelin maybe it will drown

      However more seriously based on the abstract what ever levels are achieved in the blood then 99.95% of it does not get into the CSF let alone the brain, so when you are thinking of treating a brain disease as a starting point it surely leaves loads to be desired. Now they say this in animals the levels are just as bad..but they will argue that enough gets in to do the business.

      If it works and you can make a pharmacological drug then more is bound to get more in and perhaps do a better job. However if it doesn't work will it be because not enough gets in or because it is a duff idea?Will any other company try again?.

      Now you can argue that more will get into CNS in MS but do demyelinated lesions leak sufficiently. In animals when the regent was tested the timing of blood brain barrier breakdown is known. Maybe in the trials they could image before drug delivery which would put in into active lesions that may be easier to remyelinate

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    2. The next awkward question is how long so you need room give the drug for.
      Pharmacy will want it all the time but surely you only need to kick start the repair. If you have inflammation in check. Surely a pulse treatment would be enough.
      Next awkward question if you have inflammation in check do you now get repair. If you do then this approach is not needed.
      The answer is outthere. What happens to ms lesions in people who die from PML .
      Is there remdelineation. We recently posted where they could see ms lesions did they look for remediation. In three other cases they did not find ms lesions were they all repaired. Maybe a pathologist should do a proper study. Because if there is adequate remyelination it is big news

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  2. I have no basis for this other than hopeful optimisim but I have a good feeling about the anti-Lingo1 drug in development... My view of the future of MS treatment - barring some miracle cure - is that it will be a combination of immuno (eg Alem), neuroprotection (eg BG-12) and a myelin stimulator (eg anti-Lingo1). Taken together, these or similar wouldn't be a 'cure' per se but might dramaticaly reduce the impact of MS for the majority of people. I also don't think that scenerio (perhaps anti-Lingo1 aside) is that far away either.

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  3. Why not develop a drug that is infused into the CSF? If it remyelinates it may be a necessary inconvenience if you can reverse some of the damage in progressive msers.

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    1. excellent suggestion, the intrathecal route is expensive to do

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    2. Expensive is being on a DMT for many years. Expensive is also dealing with disability due to the limited efficacy of current therapies.

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    3. I agree with you totally, but the point I was making is that intrathecal baclofen verses oral baclofen for example is a massive price and surgical differential and that leads to rationing within the NHS. However if you only need one infusion then it is the difference between a Sprotte and a Quink needle

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