Remyelination in MS
Anna Williams. MRC Centre for Regenerative Medicine, University of Edinburgh
Open Door - August 2012 pages 8-9
In multiple sclerosis, immune cells, which normally protect us from infection, attack the body's own cells instead - an autoimmune reaction. These immune cells cross from the blood to the brain and spinal cord and then damage the myelin sheath surrounding nerves. Myelin helps the nerves to conduct signals quickly and also protects them from damage, similar to the plastic insulation on electrical wires. Cells called oligodendrocytes make myelin which wraps around the nerves. When immune cells damage the oligodendrocytes, the myelin disintegrates - a process called demyelination. These areas can usually be seen on MRI scans as an MS plaque or lesion. This leaves the nerves poor at conducting electricity, causing MS relapses. The type of symptoms in the relapse depends on what part of the brain or spinal cord is demyelinated.
Most MS relapses either get better or improve greatly when the immune reaction subsides and the demyelinated lesion repairs itself. This process of remyelination is carried out by a type of stem cell present in all of us called an oligodendrocyte precursor cell (OPC). In response to demyelination, OPCs multiply, migrate to the area of damage and then mature into an oligodendrocyte which makes a new myelin sheath to surround the nerves again - a process called remyelination.
Remyelination happens frequently early in MS but gets less efficient with time. Eventually most MS lesions are not fully remyelinated. Remyelination not only restores the ability of the nerve to conduct electrical signals, but also helps to protect the nerve from damage. If nerves die back or degenerate, they cannot be replaced and this causes the accumulation of permanent disability in progressive MS.
Helping remyelination
One approach to protect nerves from dying back is to promote their fast and efficient remyelination. There are now disease modifying drugs available that can be effective in reducing the number of relapses in people with MS, but there are none that slow, stop or reverse progressive disease or neurodegeneration. Finding such drugs is now a major research aim.
In tissue from brains donated to the MS Tissue Bank, we find two sorts of MS lesions that have failed to remyelinate - those that do not contain enough OPCs (a failure of migration) and those that contain lots of OPCs but few mature oligodendrocytes (a failure of maturation).
In experimental models, increasing both OPC migration and maturation improves remyelination and remyelination reduces neurodegeneration. Many research labs have tried to discover ways to improve remyelination in these models with the aim of being able to produce drugs that can do the same in humans.
My research group has helped to discover two groups of molecules which help improve remyelination - the semaphorins which alter OPC migration to demyelinated lesions and RXRg which changes OPC maturation. There are now at least four other molecules which improve OPC maturation and remyelination in animal models, which have all been identified in the last five years. One of these molecules (antibodies against LINGO-1) is currently being tested in a very early trial in people with MS, and other trials will certainly follow. All of these aim to improve remyelination using our resident OPC stem cells.
Will stem cells help remyelination?
We know that injecting OPCs directly into demyelinated lesions in animal models leads to remyelination. There is less enthusiasm about using stem cells injected directly into the brain as MS therapy. Most people with MS have many lesions which increase over time, which would require repeated injections on several occasions with risks from the surgery and an unknown risk from the cells themselves. Improvement of remyelination using our own resident stem cells is much more likely to be successful, at least in the near future.
We also know that infusing a different type of stem cell (mesenchymal stem cells) into some experimental models of MS causes the release of helpful repair molecules which suppress the immune reaction and improve recovery. Trials for mesenchymal stem cells in people with relapsing remitting MS are in progress, but it is unclear whether these will help remyelination, which is needed in people with progressive disease.
My research group has set up an experimental model of remyelination that we can study in a culture dish, to rapidly screen many drugs and molecules to see whether they improve remyelination. We take slices of brain and grow them in a culture dish. We then demyelinate them with a toxin and study the rate of remyelination by adding different drugs or molecules to the slice. This has the added advantage of avoiding live animal use, and we recently won a 'highly commended' prize from the National Centre for Replacement, Refinement and Reduction of Animals in Research for this development. Importantly, it means that more research questions can be answered from fewer animals.
Measuring remyelination
One of the problems of moving these findings into humans is that we are different from other animals, which do not get MS. We use experimental models to try to produce a disease similar to MS, but unlike humans, rodents are extremely good at remyelination. Another problem is that it is very difficult to detect remyelination in living people. Currently, we can only be sure that areas of a lesion are remyelinated by studying tissue removed from the brain under a very high power microscope - an electron microscope. MRI scans can show MS lesions, but it is difficult to be sure which are demyelinated and which remyelinated. We also cannot tell which of these lesions contain few and which contain many OPCs, so it would be unclear whether to use therapy to promote OPC migration or maturation.
The best way currently to see whether a drug helps progressive MS is to measure the rate of worsening of disability, but this is often rather slow, occurring over several years, and testing lots of drugs in these long trials would be very expensive. So, we need to develop better models and better markers of remyelination in humans to speed up research into reducing MS progression.
In the future, I envisage that a person with relapsing remitting MS will be treated first with existing disease modifying drugs to reduce the immune attack and relapses. To avoid progression of disease, he/she will also have drugs to improve the efficiency of remyelination and perhaps a third set of drugs to further protect nerves. These are not yet available, but we (and many others) are working on it.
More about MS research
For more about research into all aspects of MS, visit the MS Trust's Research web pages. These include news about treatments in development for all types of MS, details of MS Trust funded studies and information about how to take part in trials.
Visit www.mstrust.org.uk/research
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