Thursday, 23 April 2015

More Remyelinating Drugs

Najm FJ et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo Nature (2015) doi:10.1038/nature14335

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

In this study there was a another look-see to find if one could find drugs that can promote oligodendrocytes to produce myelin. There was a panel of 730 drugs in the NIH pot that are safe in humans that can be used for repurposing. 

In this study they found 20 out of the 730 drugs did this, which is amazingly high. Good news was one was Benztropine which was found when this type of approach was investigated before. Four of the 20 were shown to promote myelination in brain slice cultures and occurred in two classes of drugs one (miconazole) was an anti-fungal drug , hence the BBC lead that "Athletes foot treatment cures MS"......yawn. This is used as a cream but sometimes as a pessary at about 3mg/kg and was used in this study at 10-40mg/kg (It causes birth defects at 60mg/kg in rodents).  

The other is clobetasol which is a corticosteroid. In humans it is also used as a cream and causes birth defects in animals at a dose of 0.003-0.1mg/kg and so in this study they used 2mg/kg. 

These drugs could both promote remyelination after chemical demyelination. This effect appeared to be mediated by the glucocorticoid receptor, and both drugs enhanced myelination of human cells they were then used in EAE and clobetasol was immunosuppressive as would be expected of a corticosteroid whereas miconazole did not stop disease but facilitated better recovery and appeared to do a better job than benztropine.

So two more candidates for treatment of MS, but unfortunately
as the authors say miconazole and clobetasol are currently only approved for topical administration in humans and topical dosing was not tested in this study.  


So significant optimization of dosing, delivery, and potentially chemical structure will be required to enhance the on-target pharmacology in OPCs while diminishing any potential off-target side effects.  The change now will be to see how these compare with high dose biotin, which maybe does the same thing and is 5-10 years down the line.

P.S. To all the visitors that have come through from clicking the altimetrics on the paper, just a note to say it is Good to see that Nature reviewers still support the use of parametric statistics on non-parametric data. They are happy to get authors to spend a year doing revisions without doing some simple things:-)

Baker D, Lidster K, Sottomayor A, Amor S.

Does it matter you ask?..maybe not in this instance, but it can do!

http://multiple-sclerosis-research.blogspot.com/2015/03/education-dont-believe-every-thing-you.html

6 comments:

  1. Well how this compares to CDP choline which is shown to be extremely safe in humans, although still no trials in MS (would they ever be?..)

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  2. Random question; On the top of your pyramid (above inflammation, neuro protection and remyelination) you have repair/restoration. What's going on in this space - anything upcoming?
    Thanks!

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    1. I dont know. ...we just had first news of neuroprotective and repair agents

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  3. Firstly, good news that a screen of compounds has identified possible candidates for OPC generation to oligos. But it seems like this is a recurrent theme. The candidates are identified but the development is never done. Either academia can't or won't due to lack of funds and pharma seems disinterested unless they can make $$$.

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    Replies
    1. Absolutely wrong..see Dr Benn talk tomorrow, however it is a fact that it takes a long time to develop and fund an academic trial

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    2. Hopefully I will be wrong and some of these drug candidates will be developed

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