Tuesday, 8 July 2014

A quick screen to find a myelination drug.

Mei F, Fancy SP, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJ, Green A, Hauser SL, Chan JR Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.

Nat Med. 2014 Jul 6. doi: 10.1038/nm.3618. [Epub ahead of print]

Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of anti-muscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.



The search for remyelinating treatments is a hot topic at the moment. The question is how do we find them?

Well one thing that is needed is a screening assay with a read-out, e.g. myelination and then you screen thousands of compounds until you get a hit ( a compound that promotes myelination).

Then you can develop other compounds around the hit. I heard a pharma talk last week and they screened 860,000 compounds to find drugs that hit their target (about 2000 out of 860,000.

Academics don't have the resource to do this but have the brains to come up with the assays for the screens.

In this study they screened a 1000 compounds in their new assay.

It is a consists of the production of a synthetic cone. When an oligodendrocyte wraps myelin round the cone to produce a ring of myelin, which can be detected.

They found a muscarinic (acetyl choline) receptor blocker promoted myelination.

Why is this approach exciting (a) because they have developed a way to test a lot of chemicals and more importantly (b) they found the same target identified is another study using a completely different screening process approach.

This suggests they are one to something
http://multiple-sclerosis-research.blogspot.com/2013/10/anti-acetyl-choline-drug-promotes.html

They have found a drug already used in humans, not without the potential to cause side effects with long-term use. I believe trials are already started.

Check out the this post for some nice pictures from the actual paper and details of the trial (click here)

4 comments:

  1. Muscarinic receptor antagonists such as trospium is/are used for spastic bladder. Maybe good for bladder control and promote remyelination, not bad. I bet pharma will be screening these compounds for re-myelination potential. But the inflammatory environment still has to be addressed. They can screen drugs using these arrays but will they work in an inflammatory environment?

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    Replies
    1. Will they work in an inflammatory environment..i don't know? The most relevant tests have not been done.

      Maybe you can deal with inflammatory environment using a different agent

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    2. I might have remembered this wrong, but didn't you say if you don't deal with the inflammation first before re myelination , it's like putting wood on a burning fire.

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    3. Yes i did say that so the trial design is important if not critical. History has shown us that we have to learn what that design is in reality using the optic nerve and visual system is the best candidate.

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