Tuesday, March 25, 2008

World of MS - Resources - Remyelination, the next treatment target for MS?

MS in focus Issue 11 - 2008

Robin J.M. Franklin, Professor of Neuroscience and Director of the UK MS Society Cambridge Centre for Myelin Repair, University of Cambridge, Cambridge, UK

A section from the brain of a person with MS. Within the dark blue staining region (white matter) the pale (white) areas are demyelination - the pale blue areas are remyelination. Adult stem precursor cells (above) give rise to new myelinating cells in remyelination.

What is remyelination?
The nervous system works because nerve fibres (axons) convey information between nerve cells (neurons) by way of electrical impulses. Their ability to do so is greatly enhanced by an insulating sheath that wraps around the nerve fibre. This sheath is made by a substance called myelin and in the CNS – the brain and spinal cord – myelin is made by a cell called the oligodendrocyte. In MS the oligodendrocyte and the myelin sheath it makes are a major target of the disease process. Loss of oligodendrocytes leads to loss of myelin sheaths from around axons – a process called demyelination. The immediate consequence of demyelination is that the axons become considerably less efficient at conducting impulses. However, demyelination may be followed by a spontaneous regenerative or healing process in which new myelin sheaths are restored to the axons. This process is called remyelination or myelin repair, although this term suggests that damaged myelin gets patched up – which is not really what happens – and enables the axons to resume efficient impulse conduction.

Why is remyelination important?
Remyelination is the normal response to demyelination and was first shown to occur in MS many years ago. More recent studies have shown that in some patients, remyelination can be very widespread and extensive. However, for reasons that are currently far from clear and are likely to be multiple, remyelination is sometimes incomplete or fails altogether. This means that axons remain permanently demyelinated; a serious situation since in this state they become very vulnerable to death themselves. A view widely held by MS researchers is that the progressive loss of chronically demyelinated axons accounts for the progressive and largely untreatable deterioration experienced by nearly all MS patients. Preventing axonal loss is therefore a major therapeutic objective which, it is hoped, will allow treatment of stages of the disease for which none currently exist, and that will slow down or even arrest deterioration. Since myelin appears to be important for maintaining the health of the axons, many experts in the field believe that the therapeutic promotion of remyelination in situations where it has failed may represent one of the most effective ways of preventing axon loss. Preventing axonal loss is sometimes called neuroprotection.

How might remyelination be enhanced?
Since remyelination can occur as a spontaneous response to demyelination, one approach to its therapeutic enhancement is to persuade the body’s own remyelination mechanisms not to give up but to work more effectively. This is sometimes called the endogenous approach. Another approach is based on the argument that because endogenous healing has failed it needs some external help, which can be provided in the form of transplanted cells that are able to make new myelin. This is sometimes called the exogenous or cell therapy approach and is currently viewed by some as being more appropriate for rare genetic diseases of myelin rather than MS. A third, combined approach also exists in which transplanted (exogenous) cells are used to enhance endogenous remyelination. This approach is still in its infancy, but certainly has much potential. Recent experimental evidence suggests the remarkable possibility that transplanted cells, easily delivered into the blood stream, not only encourage endogenous repair but are especially effective at preventing damage occurring in the first instance by damping down the damaging inflammatory response that characterises acute MS episodes (relapses). An attraction of the endogenous approach is that it may be amenable to drug-based treatments. In order for this to be developed it is necessary to know why remyelination fails so that the faulty aspects can be identified and corrected. However, in order to do this it is important to understand how remyelination works. By analogy, it is very difficult to mend a broken car engine if you have no comprehension of the engine’s internal workings.

How does remyelination work?

Remyelination is mediated by a population of stem cells that are abundantly distributed throughout the entire adult CNS. These cells are often referred to as oligodendrocyte precursor cells or OPCs. When demyelination occurs, all the OPCs in the vicinity are stirred into action. This event is called activation and involves the cells increasing their responsiveness to factors generated by demyelination that make them move around and make copies of themselves. Very quickly the area of demyelination is filled up with OPCs, a process called recruitment. The next step is for these cells to become replacement oligodendrocytes that make new myelin sheaths around the demyelinated axons. This process is called differentiation. Thus, remyelination is the result of a two-stage process of OPC recruitment and differentiation. Over the last few years scientists have been busy identifying the multitude of factors involved in OPC recruitment and differentiation. Some of these are environmental factors to which the OPCs are exposed; others are factors within the OPCs that allow them to make the appropriate responses to environmental factors. While much has been learnt it is apparent that there is still a great deal more to be understood. The number of factors is very large and most work in complex networks, making the process an immensely complicated one to understand completely.

Why does remyelination fail?
In theory, remyelination might fail because of a failure of either OPC recruitment or differentiation, which would determine whether remyelination therapies were to be based on the provision of recruitment or differentiation factors. Differentiation seems to be the more complicated of the two processes, and therefore the one most likely to go wrong. It is therefore of little surprise that recent evidence shows that a common cause of remyelination failure in MS patients is not an absence of OPCs (these are often present in abundance) but due to the OPCs failing to differentiate into remyelinating oligodendrocytes. At what stage is remyelination research? Because remyelination appears to be failing at the differentiation stage, at least in a proportion of damaged areas in a proportion of patients, many scientists are currently focusing on how differentiation works and how it might be promoted. There are two possible explanations for differentiation failure and either or both of which may be possible: differentiation may fail because of an absence of factors to enhance it or the presence of factors that inhibit it. Several possibilities for both explanations are being investigated. These studies usually take the form of laboratory-based studies, using various animal models and cell cultures, and studies of post-mortem tissue from MS patients, which is becoming increasingly widely available thanks to the setting up of specific MS brain banks. An excellent example is the one funded by the UK MS Society based at Imperial College in London. The results obtained from the two types of studies mutually inform each other – the post-mortem tissue pointing the way to the laboratory studies and the laboratory study giving clues as to what one might expect to find in post-mortem material. This work is progressing on many fronts via an increasing number of researchers and research groupings.
Although patient-based studies are currently in progress to establish ways in which enhanced remyelination can be monitored and assessed in patients, remyelination research is still at present an essentially laboratory-based endeavour. This is inevitable considering the complexities of the problem and it is worth remembering that there are very few currently available treatments to enhance regenerative process for any tissue in the body, let alone the CNS. Nevertheless, scientists and clinicians involved are optimistic that in the future the availability of remyelination therapies will have a significant impact on the treatment of MS, given the pace and momentum that this important area of research has acquired in recent years

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