A recent review has outlined the progress made so far in understanding the biology of remyelination, what goes wrong in MS, some of the research problems that need to be tackled and the prospect for treatments in the not-too-distant future.
Considerable progress has been made in understanding the biology of remyelination. This has identified potential treatments, such as clemastine, opicinumab and bexarotene which are being tested in clinical trials.
The review shows that a good deal of progress has already been made, although there is still much to be done. The authors finish by identifying questions that further research needs to address in order to build on this work.
The review in more detail
Treatments for MS have come a long way over the last two decades. There is a growing list of drugs for relapsing remitting MS, with Ocrevus now approved for primary progressive MS and siponimod going through assessment by the European Medicines Agency. All of these drugs act by reducing the immune attack which causes inflammation and damage to the myelin coating around nerve cells in the brain and spinal cord.
Although these drugs can reduce damage to myelin, they can’t stop it completely or repair damage that has happened. Your body can replace damaged myelin but this process is impaired in MS. Treatments which promote remyelination would offer the potential to delay, prevent or reverse disability and a great deal of research is exploring this. A recent review has outlined the progress made so far in understanding the biology of remyelination, what goes wrong in MS, some of the research problems that need to be tackled and the prospect for treatments in the not-too-distant future.
How does remyelination work and what goes wrong?
An important first step in developing treatments is understanding how remyelination works in health. The picture that is emerging is a complex interaction between different cell types and chemicals produced by the cells.
In the brain and spinal cord, cells called oligodendrocytes produce myelin which they wrap around nerve axons, like a Swiss roll. An important focus of research has been understanding the different steps that immature oligodendrocytes (oligodendrocyte progenitor cells, OPCs) go through before they can produce new myelin.
Large numbers of OPCs are seen in demyelinated MS lesions, so one theory is that remyelination fails because these immature cells are unable to mature into oligodendrocytes capable of making myelin. However, recent research using brain tissue from people with MS suggests that remyelination is mostly carried out by pre-existing and not newly matured oligodendrocytes. Another recent study found several types of mature oligodendrocytes and differences in the ratios of these subtypes in people with MS compared to healthy people. These two studies raise questions about how well the models used to research remyelination represent the process in humans.
Electrical activity in nerves has been found to stimulate remyelination, suggesting that intact nerve axons are necessary for successful repair. Perhaps related to this is the recent finding that access to a running wheel in a lab model of demyelination improved maturation of oligodendrocytes, the rate of remyelination and the proportion of remyelinated nerve axons. Combining physical activity with clemastine (see below) further enhanced remyelination.
The debris left over from damage to myelin has been shown to inhibit remyelination so the clearance of debris by macrophages and the role of other cell types found in brain tissue, such as astrocytes and microglia, is another area of research.
Remyelination reduces with age and disease duration. This may have important consequences for designing clinical trials and deciding when in the course of MS remyelination treatments would be most effective. It may be possible to counteract some of the consequences of ageing – a recent study reported that in a lab model of demyelination, alternate day fasting or treatment with metformin, a type 2 diabetes drug which can mimic the effects of calorie restriction, can recalibrate ageing OPCs to remyelinate axons.
Remyelination clinical trials
The good news is that research is beginning to identify potential treatments which are being tested in clinical trials. However, one of the biggest difficulties for clinical trials is demonstrating that a drug is having an effect by promoting remyelination. Advanced MRI techniques and PET (positron emission tomography) scans are being developed. Another approach is to use evoked potentials to measure the speed of electrical messages along sensory nerves to the brain.
A protein called Lingo-1 prevents OPCs developing into functioning oligodendrocytes. Opicinumab blocks the action of Lingo-1, allowing OPCs to mature. In a phase II study of people diagnosed with optic neuritis, opicinumab improved transmission of nerve impulses in the optic nerve, suggesting that remyelination had occurred. A second phase II study used a combination of Avonex (interferon beta 1a) and opicinumab but found neither an improvement in disability nor a slowdown in progression. These results were disappointing, but further analysis suggested some improvement in a subset of the participants. It is now being tested in a further study as an add-on to disease modifying drugs in relapsing MS.
Another route to discovering candidates is through testing large numbers of molecules in laboratory models of OPC development. This approach identified clemastine, a drug normally used to treat allergies. In a phase II clinical trial in 50 participants with relapsing MS and evidence of long term damage to the optic nerve, clemastine treatment resulted in a small improvement in the speed at which nerve impulses passed along the optic nerve. There was a slight improvement in vision, but too small for this to be conclusive. The researchers were unable to show the repair on MRI scans and other measures of myelin. Clemastine is now being tested in a second phase II trial in people with acute optic neuritis.
The review lists further clinical trials of potential remyelinating treatments, including bexarotene, biotin and cell-based therapies, which have been completed or are underway.
This review shows that a good deal of progress has already been made, although there is still much to be done. The authors finish by identifying questions that need to be answered in order to build on this work:
- How well does remyelination in animals match the process in people with MS?
- What is the best way to measure remyelination in clinical studies?
- When would be the best time to start a remyelinating treatment?
- Which is the most appropriate group of people with MS for testing remyelinating treatments?
Cunniffe N, Coles A.
Promoting remyelination in multiple sclerosis.
Journal of Neurology 2019 Jun 12. [Epub ahead of print]
Myelin is the layer of fatty protein wrapped around the axons of nerve cells. It acts as insulation, speeding up the transmission of electrical impulses along nerve axons. Loss of myelin slows down or blocks nerve impulses and, once exposed, nerve axons can be damaged and lost.
The myelin sheath has short gaps about one micrometre apart known as Nodes of Ranvier. Nerve messages leap along the axon from node to node. The thickness of the myelin sheath and the size of the gap between nodes determine the speed of messages, which can be as fast as 120 metres/second (268mph).
Nerve cells are surrounded by support cells called glial cells. These include oligodendrocytes which produce myelin.
Find out more about nerve cells (neurons), myelin and oligodendrocytes.
