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

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.

Multiple sclerosis (MS) is a common chronic demyelinating, neurodegenerative disease of the CNS, with major societal impact. There are now effective treatments to reduce relapses in early disease, but not to slow, stop or reverse disability progression in later disease. As disability reflects neurodegeneration, one focus of research into therapies to limit progressive disease is to enhance repair of demyelinated lesions (remyelination), restoring saltatory conduction and metabolic support to the underlying axon. Three such therapies have now been tested in clinical trials but with only minor effects. This may be due to two problems: 1) we have shown that aged adult rat oligodendrocytes do not respond to these pro-remyelinating drugs compared to young adult cells, but these drugs become effective again after metformin treatment, 2) our snRNAseq from human brain shows six distinct human oligodendrocyte 'states', different from rat, the proportion of which are different in MS, suggesting it may be best to enhance particular oligodendrocyte states e.g. those better at remyelination.
We hypothesise that pro-remyelinating drug efficacy will be improved if preclinical testing is performed on aged human oligodendroglia with relevant functional states similar to those in MS. In this project, we will use adult human oligodendrocytes to determine whether remyelination declines with age and is rejuvenated after metformin treatment. Thus we need in vitro adult human oligodendrocytes, preferably from a stem cell source for a limitless supply. We will obtain some from human brain biopsies, but we will test strategies to induce 'aged' cells from stem cells. We will assess oligodendrocyte states formed under these conditions.
These drugs and metformin are being considered for use in the MS Society UK's 'Efficient Clinical Trials Platform'. This project will provide a relevant testing platform for current and future drugs, accelerating movement of effective drugs into MS patients.

Who will benefit from this research and how?

MS patients
There is an unmet need for therapies for progressive MS patients, but the MS Society UK is committed to providing 'The Efficient Trials Platform' which will test new therapies for progressive MS in an adaptive trial design. There is a list of potential candidate drugs for trial within this from preclinical work. We believe this project will allow better selection of these drugs for myelin repair singly and in combination on disease-relevant human cells, with all likelihood of a bigger clinical effect in patients. If any treatment works in progressive MS, the societal impact is large.

MS researchers
This research will answer the questions as to whether aged/adult human oligodendroglia are poorer at remyelination and the mechanisms as to why, if they can be rejuvenated in vitro and whether they can be modelled using stem cell-derived oligodendroglia. We will share techniques of human OPC culture, conversion to aged/adult cells in vitro, and in vivo human OPC transplants. We will generate single cell/nuclei RNAseq data which will be made publicly available.

Private sector companies e.g. pharma:
There will be interest in using the best type of adult disease-relevant human oligodendroglia to use for screening drugs for pro-remyelinating effects.

Local, national and international policy-makers, for determining best use of funding:
There will be interest as to quickly finding which future therapies for MS (and similar diseases) are worth funding further.