What did the project achieve?
“We have successfully developed a new stem cell model of Charcot-Marie-Tooth disease,” says Professor David Bennett of the University of Oxford. “This offers huge potential for improving the understanding of the biology of the disease and testing potential new treatments that could help slow down or stop disease progression.”
Charcot-Marie-Tooth disease (CMT) is a group of inherited conditions that damage the peripheral nerves, which transmit information between the spinal cord and the rest of the body. The symptoms of the condition usually start when a child is between the ages of five and 15 and slowly get worse and more disabling over time, making everyday tasks increasingly difficult.
This research focused on the most common form of CMT, called CMT1A, which is caused by having an extra copy of a gene called PMP22. This leads to damage to a substance called myelin, which normally forms a protective coating that surrounds the nerves (the myelin sheath). The team’s long-term goal is to develop a new treatment – a form of gene therapy – that stops, slows down or even repairs this damage to the myelin sheath.
“We successfully used cutting-edge stem cell technologies to create nerve cells using skin cells from people with CMT1A and healthy individuals,” says Professor Bennett. “We noticed differences between these nerve cells – the CMT1A neurons had a smaller size with thinner nerve fibres compared to healthy cells.”
The researchers then explored the ability of nerve cells to form a myelin sheath – by growing them in dishes along with a type of support cell (called Schwann cells).
“We found that patient-derived neurons had a reduced ability to interact with Schwann cells, which play a vital role in the myelination process – and this effect was independent of any faults in the support cells,” says Professor Bennett. “This surprising discovery revealed a novel disease mechanism, suggesting there is a signal from the CMT1A nerve fibres that leads to problems with myelination – opening a new research avenue for the development of targeted treatments.”
The team then tested the effects of a potential gene therapy – which involves helping cells to produce a protein called neuregulin 1, or NRG1, which plays a pivotal role in controlling the production of myelin. Unfortunately, although this treatment had shown promise in healthy cells, it did not improve myelination in CMT1A nerve cells.
“We now need to use our new stem cell model to improve the understanding of how disrupted signalling from the CMT1A nerve fibres leads to problems with myelination,” says Professor Bennett. “This will help us to identify the best therapeutic strategy to take forward.”
This research was completed on
Estimates suggest around 25,000 people in the UK have Charcot-Marie-Tooth disease (CMT).1 They usually start to have symptoms – which can include muscle weakness and numbness in the feet, arms and hands – during childhood or adolescence. Symptoms slowly get worse and more disabling over time, making everyday tasks increasingly difficult. Professor David Bennett, of the University of Oxford, is in the early stages of developing a new treatment – a gene therapy – for children with CMT. There’s no cure for CMT, and no way to slow down the progression of the disease, so improvements in treatment are badly needed.
How are children’s lives affected now?
People with CMT, an inherited condition, usually experience their first symptoms when they’re between five and 15 years old.
Symptoms vary from one child to another. Early signs of CMT in a young child can be difficult to spot. A child might just seem clumsy or accident prone, for example, or they might find it difficult to walk, because of problems lifting their feet off the ground. As the children can have high insteps, it may be difficult to get shoes to fit.
Symptoms get worse and more disabling over time, although CMT is unpredictable, so it’s not possible to tell how quickly this will happen or how severe symptoms will become.
Symptoms that can get worse include muscle weakness and some loss of feeling in the hands and arms, which make everyday tasks such as writing, doing up buttons or opening jars difficult. Children can also have problems with walking and with posture, which can put excessive strain on the body and cause debilitating pain.
How could this research help?
“Our ultimate goal is to develop new treatments for CMT,” says Professor Bennett. “At the moment, we are focusing on the most common form of CMT, called CMT1A.”
The symptoms of CMT1A result from damage to peripheral nerves, which are found outside of the brain and spinal cord. A substance called myelin, which normally forms a protective coating around nerves, is damaged, as children with the condition have an excess dosage of the gene called PMP22, which makes myelin unstable.
The team aims to develop a new treatment – a form of gene therapy – that stops, slows down or even repairs this damage to myelin. They are investigating a possible way to do this in the laboratory. “Our approach involves helping cells to produce a protein called neuregulin 1, or NRG1, which plays a pivotal role in controlling the production of myelin,” says Professor Bennett. “The aim of this project is to see if this protein can help myelination of cells derived from patients with CMT1A.”
This work is in its early stages, but a new treatment that prevents or slows down disease progression, and stops children’s symptoms from getting worse, would be a major step forward.
1. CMT UK. http://cmt.org.uk/about-cmt/what-is-cmt/ Website accessed 15 January 2017.
|Project Leader||Professor David L H Bennett MB PhD FRCP|
|Project Team||Dr Ilaria Cervellini PhD|
|Project Location||Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford|
|Project duration||3 years|
|Date awarded||21 November 2017|
|Project start date||1 January 2017|
|Project end date||28 February 2021|