A team of researchers from the US, UK and China, has developed an impressive new technology that will enable the mass screening of drug compounds to identify those that may promote repair of the myelin sheath that is damaged in the brain and spinal cords of people with MS.
The research was published in the top medical journal Nature Medicinelast week. The abstract describes the development of an array of nanofibres that can be produced in laboratory cell culture dishes. The fibres provide a scaffolding that mimics the long thin nerve fibres (axons) in the brain and spinal cord, allowing researchers to monitor the growth of myelin-producing cells in the dish and their ability to wrap the scaffolding in myelin.
Loss of myelin during the inflammatory attacks of MS leads to disruption of the conduction of messages along nerves, causing the symptoms of MS such as weakness, vision loss and pain. During periods of remission in MS, myelin can be repaired and symptoms improve, however, over time myelin repair fails and exposed axons become irreversibly damaged leading to permanent disability. Understanding how myelin repair (remyelination) may be encouraged is therefore a key target of MS research.
The process of remyelination is dependent on several steps including an increase in number of myelin-producing oligodendrocyte precursor cells, the movement of the cells to the site of damage, and finally the proper wrapping of a new functional myelin sheath around nerve axons.
The technology developed by the researchers is an array of silicon ‘micro-pillars’ contained within a typical cell culture dish, known as a 96-well plate. 96-well plates are commonly used in large automated laboratory assays in which a separate ‘experiment’ can be performed in each of the 96 miniature ‘test-tubes’ on the plate.
The structure of the silicon micro-pillars mimics the structure of nerve axons, allowing oligodendrocytes growing in the dish to move to the pillars and wrap myelin layers around the pillar, just as they would with an axon in the brain. The researchers were able to use specialised microscope techniques to observe and quantify the efficiency of myelin wrapping around the micro-pillars.
Using this technique the researchers screened a library of 1000 potential drug molecules and discovered a group of eight molecules that increased the amount of myelin wrapping. The molecules are all known to act via a similar mechanism in blocking a particular receptor molecule found on neurons, known as muscarinic receptors.
Of particular interest, two of these molecules, Clemastine and benzatropine, have previously been approved by the US Federal Drugs Administration (FDA) for other conditions and are also known to cross the blood brain barrier – an essential prerequisite for a drug intended to repair damage within the brain.
The researchers went on to show that Clemastine was able to increase remyelination of axons in a mouse model of myelin damage, and may be worth pursuing in pre-clinical and clinical studies for MS.
The researchers say that they are confident that expanding the use of the technology to screen larger chemical libraries, including more FDA-approved compounds and new molecules, will result in the identification and development of new therapies for repair in multiple sclerosis.