At some point in an MND patient’s life, their motor neurones start to die, leading to muscle wasting and eventually death – typically within two years of diagnosis.
Disruption in the ability of central nervous system to create energy is thought to be a major contributing factor and could influence disease progression rates.
But scientists in Sheffield have discovered an intervention that could potentially accelerate energy production in the central nervous system and encourage brain cells to better support motor neurones, thus limiting the disease’s progression.
They converted skin cells into brain cells called astrocytes – star-shaped brain cells that play a key role in supporting motor neurones by acting as a crucial source of energy in the central nervous system.
They then compared the energy metabolism of cells taken from MND patients versus healthy controls. This was made possible using new “metabolic phenotyping” technology developed by Biolog, Inc, a Californian biotech company.
As a result, the University of Sheffield’s Institute for Translational Neuroscience (SITraN) researchers discovered the loss of a key enzyme that could have major consequences for how the central nervous system copes with ageing, stress and loss of energy metabolism.
Working in collaboration with Biolog, Inc., they sought differences in the metabolism of astrocytes from MND patients.
Dr Allen, a Motor Neurone Disease Association-funded senior researcher, found that cells from MND patients had reduced ability to turn a metabolic substrate called adenosine into energy due to loss of an enzyme called adenosine deaminase.
The consequence of this loss could be a toxic build-up of adenosine in the central nervous system and subsequent loss of inosine production, a metabolic intermediate that is generally protective.
Until now, the link between MND and inosine production through the loss of adenosine deaminase had not been made. When Dr Allen fed the brain astrocytes inosine, energy production increased and the patient’s astrocytes became more supportive towards motor neurones, helping them to live longer.
Dr Allen says: “We are really excited about this set of results as no one has implicated adenosine deaminase in MND before.
“Our results indicate that the higher the level of adenosine deaminase, the greater the protection against adenosine mediated toxicity and the greater support towards motor neurones when given inosine.
“Although we are at an early stage, I think increasing adenosine deaminase levels, combined with inosine supplementation has the potential to slow down disease progression in MND patients. But a lot of further testing in the laboratory has to be performed.”
Altering the level of adenosine deaminase by gene therapy has previously been shown to be beneficial and safe in patients suffering from severe combined immunodeficiency disease.
Inosine is a safe and readily-available nutritional supplement, which has been successfully tested in Parkinson’s disease patients. There is therefore hope that, in the future, this combination of treatment could work in people with MND, improving their quality of life and helping them live longer.
Meanwhile, a separate study has raised the prospect that statins could help to protect against MND.
It stems from the discovery that high cholesterol could be a possible risk factor for the development of motor neurone disease (MND).
This is according to a large study of genetic data led in the UK by Queen Mary University of London, in collaboration with the National Institutes of Health in the US.
The results suggest that cholesterol-lowering drugs, such as statins, could be used to prevent the onset of MND, if confirmed in clinical trials.
Dr Alastair Noyce, from Queen Mary’s Wolfson Institute of Preventive Medicine, say: “This is the largest study to-date looking at causal risk factors for motor neurone disease and we saw that higher levels of LDL cholesterol were causally linked with a greater risk of the disease.
“We have well-established drugs that can lower cholesterol and we should look into whether they could protect against this terrible disease, which currently has no cure.
“The next steps will include studying whether lowering levels of cholesterol might have a protective effect against MND, and potentially evaluating the use of cholesterol-modifying drugs in people at risk of MND.”
Published in the journal Annals of Neurology, the team searched genetic datasets of around 25 million people (including more than 337,000 people from the UK Biobank) to find risk factors for developing MND.
While the datasets did not contain data on individuals’ actual cholesterol levels, the team studied genetic markers that are linked to cholesterol levels, and are more likely to suggest a causal link with risk of MND rather than simply associations, which are usually reported from observational studies.
A randomised control trial would be the definitive proof to confirm any causal link and the ability of statins to prevent MND.
In addition to the causal effect of high cholesterol, they also found genetic associations with smoking behaviour and lower levels of educational achievement, and an increased risk of MND.
While low levels of exercise were associated with a protective effect, more aggressive exercise was associated with increased risk. However, of these findings, only high cholesterol emerged as a clear modifiable factor that could be targeted to reduce risk of MND.
The research was carried out at Queen Mary’s Preventive Neurology Unit, which has been funded by Barts Charity.
MND treatments could be developed following new research
Pioneering treatments could be developed for people with motor neurone disease (MND) after a new study shed light on how the damage to nerve cells can be repaired by improving the energy levels in mitochondria.
Researchers have discovered that, in human stem cell models of MND, the axon – the long part of the motor neuron cell that connects to the muscle – is shorter than in healthy cells.
The laboratory study also found that the movement of the mitochondria, which travel up and down the axons, is impaired.
This was caused, the study found, by a defective energy supply from the mitochondria and that by boosting the mitochondria, the axon reverted back to normal.
The study was led by Dr Arpan Mehta alongside Dr Bhuvaneish Selvaraj and Professor Siddharthan Chandran from the Euan MacDonald Centre for MND Research at the University of Edinburgh.
The researchers used stem cells taken from people with the C9orf72 gene mutation, which causes both MND and frontotemporal dementia. They used these stem cells to generate motor neuron cells in the laboratory to use in their experiments.
The study also examined human post-mortem spinal cord tissue from people with MND who had donated their tissue through the Medical Research Council Edinburgh Brain and Tissue Bank. The results supported the findings from the stem cells.
MND, also known as amyotrophic lateral sclerosis or ALS, is a progressive condition that causes muscles to waste away. It occurs when nerve cells called motor neurons, which send messages from the brain and spinal cord to the body’s muscles, stop working properly.
More than 1,500 people are diagnosed with MND in the UK each year, but no cure has yet been found.
Although the research focused on the people with the commonest genetic cause of ALS, researchers are hopeful that the results will also apply to other forms of the disease.
The results of the study are now being used to look for existing drugs that boost mitochondrial function and may be able to be repurposed to treat MND.
Dr Arpan Mehta, Lady Edith Wolfson Fellow and PhD student at the University of Edinburgh, said: “The importance of the axon in motor nerve cells cannot be understated.
“Our data provides hope that by restoring the cell’s energy source we can protect the axons and their connection to muscle from degeneration. Work is already underway to identify existing licensed drugs that can boost the mitochondria and repair the motor neurons. This will then pave the way to test them in clinical trials.”
The study was funded by the Medical Research Council, Motor Neurone Disease Association, Euan MacDonald Centre for MND Research, My Name’5 Doddie Foundation, UK Dementia Research Institute and Anne Rowling Regenerative Neurology Clinic.
High rollers lead MND tech development
Rolls-Royce through its data technology arm, R2 Data Labs, has partnered with the Motor Neurone Disease Association and some of the world’s leading technology companies, including Accenture, Computacenter, Dell Technologies, Intel and Microsoft, to pool technology and expertise to improve the lives of those living with extreme disabilities.
For the first time, those living with MND will be able to have a conversation through a computer using their own voice, words, colloquialisms and accent, without pausing to type answers or being restricted to a prescribed set of words.
The new technology, called Quips, uses voice-banking and AI to learn a person’s unique language style and use it in conversation.
Communication is one of the most difficult aspects of living with motor neurone disease, which affects around 400,000 of the world’s population and kills more than 100,000 people every year.
Nick Goldup, director of care improvement for the MND Association, said: “MND affects the nerves in the brain and spinal cord which tell muscles what to do. As the disease progresses people lose the ability to move, eat, speak and eventually to breathe.
“The technology available to help people communicate has changed little in the recent past – most people will be familiar with Professor Stephen Hawking’s computerised voice which he programmed using his eyes. This technology will allow people living with MND to communicate closer to ‘real time’ than they can with existing technology.”
Quips is in its early stages, but Rolls-Royce is aiming for it to be implemented into some of the leading augmented and alternative communication packages that already exist, such as those used by the late Professor Stephen Hawking.
Currently, users type what they want to say, and the words or phrases are read out, often in a computerised voice. Quips listens to the conversation, suggesting words and phrases that the user is likely to want to say, based on its understanding of their previous conversations.
The user can quickly select sentences and they are read out in their own voice instantly, with their own accent and local colloquialisms, without gaps for typing.
It even includes slang and can adapt to different situations and people, such as work, home, or even the pub.
Goldup said: “Having your voice stripped away is one of the most brutal aspects of MND. Technology that allows people to retain those things that make them unique – their voice, speech patterns, intonations and word choices – is a huge leap forward in enabling someone to retain their dignity and their sense of self.
“This is really exciting technology – and of course its potential use expands much further than just people with MND.”
Stuart Moss, an IT Innovation strategist at Rolls-Royce, lost his father to MND on Christmas Day 2014.
He started the Next Generation Think Tank earlier this year, alongside the Motor Neurone Disease Association.
Stuart said: “Those with MND are often robbed of their ability to communicate with their loved ones, which can make the festive season particularly lonely and difficult. This technology will give people their voice back and is the first step in what I hope will be many innovations to come from the Next Generation Think Tank.”
MND research portal launched
A new online resource providing “accessible” motor neurone disease information has been launched.
The UK Motor Neurone Disease Clinical Studies Group has launched an updated version of its online portal.
It enables users to find out about all the MND clinical research studies taking place across the UK..
The MND CSG’s aim is to “bring together expertise and enthusiasm to develop and improve both the quality of MND research in the UK, and the number of research studies available for people living with MND to participate in nationally”.
The Group currently includes 36 members with leading MND neurologists, palliative care specialists, patient and carer representatives and other healthcare professionals with an interest in MND clinical research.
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