Do adult human oligodendrocytes remyelinate poorly and can we change this to better treat progressive multiple sclerosis?

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Multiple sclerosis (MS) is a common chronic disease of the brain and spinal cord, often starting in young adulthood, which frequently causes disability. Although the early stages of the disease can now be controlled with medication, in the later stages, there are no treatments to either slow, stop or reverse disability. One focus of research to help the later 'progressive' phase of MS is to encourage repair of the myelin sheath that covers the nerves. This is damaged in MS and when replaced can protect nerves from dying. The cells that carry out repair of this myelin sheath are called oligodendrocytes, which are present in brains of people with MS, but these cells struggle to repair the myelin sheaths. Researchers have now developed drugs that might help oligodendrocytes to repair myelin sheaths but in trials in people they only showed a very small effect. This project will investigate ways to improve this effect.Firstly, we now know that rat oligodendrocytes are worse at repairing myelin as they get older, and most drugs are tested in the lab on very young oligodendrocytes. We found that these drugs currently being tested in clinical trials do not help adult brain oligodendrocytes repair myelin. However, these drugs become effective again if they are first treated with another drug called metformin. Secondly, we recently found that there are different types of human oligodendrocytes, which are different from in rat oligodendrocytes, and some of these types might be better at repairing myelin than others.In this project, we will test whether adult human oligodendrocytes also become worse at repairing myelin with age, and can be rejuvenated to respond better to the pro-repair drugs with metformin. To do this we need to be able to grow adult human oligodendrocytes in a dish. We will obtain some from human brain biopsies, but also we will try and make 'aged' cells from stem cells (which normally represent very young cells) by using genetic tricks. We will also see whether we can use this method of rejuvenation in combination with drugs to help encourage the formation of the best type of oligodendrocytes for myelin repair.This project will find out whether we can better test MS therapies on relevant adult human cells, to improve their response to drugs helping myelin repair. Some of these pro-repair drugs and metformin are being considered for use in 'The Efficient Clinical Trials Platform' to be launched by the MS Society UK in 2020, and so this project will help select some of these current drugs and provide a relevant testing platform for other drugs. This means we will better at finding drugs that are more likely to work in MS and can test them in MS patients quickly.