Edaravone trial presentation sparks interest

Bar a few bacteria usually found hitching a ride on our dental plaque and digestive system, every living cell in the human body needs oxygen. Some cells need more oxygen that others, dependent on much energy they need to produce to function. Neurones are particularly active cells (the brain uses a fifth of all the oxygen consumed by the human body) and motor neurons are amongst the most energy hungry of all.

Unfortunately, the process of producing cellular energy isn’t 100% efficient: a small but constant amount of waste products called free radicals (yep, those things that the beauty product industry bangs on about) can build up in the cells. If not kept in check, they can start to wreak havoc within the cell.

Our cells have quite effective ways of dealing with free radicals, but these ‘cellular defences’ become less and less efficient with age. As we age, our energy production processes lose efficiency, causing a ‘double-whammy’ of not only more free radicals being produced, but also less effective ways of dealing with them. When neurones are damaged, as happens with neurodegenerative diseases, then everything gets exacerbated even further, leading to a vicious cycle of events.

It’s a bit like sparks escaping from a campfire – if there are too many sparks and you don’t keep an eye on things, you can end up with the forest ablaze. Sparkler

This series of cellular events is commonly known as oxidative stress and there is plenty of evidence that it plays a role in motor neurone disease (MND) and other neurodegenerative diseases. However, turning the theory into treatments has proven difficult. Several antioxidant treatment strategies have been tested in clinical trials, but none have been effective. But maybe there are signs that things are changing.

Edaravone trial in MND

Japanese clinicians working with Mitsibushi Tanabe Pharma ran a 9 month study of the free radical scavenger Edaravone, which is used in the treatment of stroke. They presented their results on the final day of the Symposium.

Chemical structure of Edaravone

Chemical structure of Edaravone

The trial involved over 200 MND patients (half taking the drug, half on placebo). The trial, however, did not show any statistically significant benefit, although there was a trend towards slower progression with the drug. This hint of an effect led the investigators to analyse the data more thoroughly and they identified a subgroup of patients that appeared to obtain some benefit.

There is a saying that “if you torture your data long and hard enough, you can make it tell you anything” and this is particularly true in medicine, where such ‘post hoc analysis’ is always taken with a large pinch of salt. The next step therefore was to carry out a further study focused on the particular subgroup of patients. Over 130 participants took part in this trial, receiving intravenous infusion of Edaravone. The results showed a statistically significant slowing of disease progression (assessed using the Revised ALS Functional Rating Scale) over the 24-week treatment period.

Whilst these results give a glimmer of hope after so many years of negative and inconclusive trials, there are some questions that need to be answered. Why does the drug only appear to show some effect in a subgroup? Can the trial results be confirmed and, if so, can a longer term effect be demonstrated? Does the drug have an effect on survival? In addition, the drug has to be given intravenously, which may be impractical for many, plus there are key differences in the way that the Japanese population metabolises drugs compared with Caucasians, so very different doses may need to be considered for different populations.

Hopefully, some of these questions will be answered through another study. The Dutch company Treeway  is developing a formulation that can be taken orally and has been shown to be safe in preliminary (Phase 1) studies. The company is aiming to start a phase 2/3 study in 2016.

More information on the clinical trials process can be found on our website or in our research information sheet.

New ALS gene represents another small step

It wouldn’t be the Symposium without a new gene discovery.

Although technology has allowed incredible advances in the gene-hunting field, this is countered by the fact that as more and more familial amyotrophic lateral sclerosis (FALS) genes are found, it makes the search for the remaining unknown genes harder  This is in part due to the fact that the undiscovered genes are likely to be increasingly rare (so even more rigorous detective work is needed) but the challenge is compounded by the fact that there are fewer and fewer samples with an unknown cause available each time a new gene is found.

The solution to these problems lies with greater collaboration, sharing knowledge, expertise and of course the vital samples needed for the research to happen.Dr Brad Smith

Dr Brad Smith (King’s College London) unveiled the latest collaborative effort, involving over 50 researchers across 9 countries. The researchers took an approach called Exome Sequencing, which analyses the 1% of the genetic code where most mutations are likely to be found, to look for genes in several hundred FALS cases where the genetic cause was still unknown. They then compared their findings with those from 60,000 individuals in publicly available databases.

After this major piece of number crunching they were left with a long list of possible FALS genes, which is forming the basis of further follow-up studies. Dr Smith was reporting on one of these, which appears to account for 1-2% of FALS. Variants of the gene also appeared in a similar proportion of sporadic ALS, suggesting that in some cases it may act more as a risk factor rather than a single driver of disease. This is substantiated by the fact that it is associated with a relatively late onset ALS.

It is still not clear how the mutated protein causes motor neuron damage, but Dr Smith showed preliminary studies in cell cultures that indicated that the mutants appear to be involved in two processes linked to motor neuron degeneration in ALS.

To paraphrase a quote associated with Cape Canaveral, just east of this meeting, ‘another small step’ has been made. Hopefully it will help lead the scientific community closer to making that ‘giant leap’.

Spreading the seeds of an idea: MND disease pathology

With motor neurone disease (MND), the muscle weakness almost always starts in a single part of the body, with the weakness then spreading to other muscles in an orderly fashion. Neurologists are usually quite good at predicting which muscles will be affected next, slightly less so at predicting when this will happen.

The physical changes on the outside will be reflecting events occurring in the ‘closed box’ that is the brain and spinal cord. The latest imaging techniques are starting to give us more of a picture of what’s happening in the central nervous system as the disease progresses, but further technological advances will still need to be made. The clearest picture still comes from the study of generously donated and incredibly valuable post-mortem tissue.

The second day of the Symposium saw researchers present in the Clinical-Pathological Correlates of Disease Progression session, focussing on how to understand disease progression, the role of prions in neurodegenerative diseases and the relationship between MND and frontotemporal dementia.

Over many years, Dr John Ravits (University of California, San Diego) has examined hundreds of central nervous system (CNS) tissue samples from dozens of MND cases. By carefully comparing pathology with the clinical symptoms, he has managed to build up a picture of disease spread, both up and down the spinal cord as well as from one side to another.

Progressive spread of MND pathology (image courtesy of Dr John Ravits)

Progressive spread of MND pathology (image courtesy of Dr John Ravits)

How the disease propagates from one degenerating motor neuron to the neighbouring more healthy motor neurons is not well understood,  but some of the clues as to what might be going on come from another family of neurodegenerative diseases called prion diseases. Prion stands for ‘protainaceous infectious particle’ and the best known of these conditions is Creutzfeld-Jacob disease (CJD).

Prion proteins damage neurons by entering nerve cells and interacting with healthy proteins. They cause the healthy proteins to change shape, turning them into prion proteins as well, which can then escape the nerve cell to ‘infect’ another: a process that researchers call ‘seeding’.

So why are CJD and MND very different diseases if they use similar processes?

The answer is because entirely different proteins are at play in different diseases. Indeed, a ‘prion-like’ effect is not just limited to MND: it is also thought to occur in Alzheimer’s disease. Dr Mark Diamond (University of Texas) provided an overview of how a protein called ‘Tau’ appears to be the culprit for conditions such as Alzheimer’s disease and Progressive Supranuclear Palsy.

Dr Diamond has found that the spread of Tau protein occurs well in advance of any significant signs of cellular damage. He has developed a system for measuring the seeding of Tau between cells and finds that different ‘strains’ of Tau protein appear to be associated with different types of disease. The different patterns of strains could also feasibly help to speed up diagnosis in the future.

In addition, if the protein involved in Alzheimer’s disease is different, but the basic process of disease seeding and spread is the same, then similar strategies could be used for different diseases – each aiming at a different specific protein target.

So what is the ‘prion-like’ protein involved in MND?

There may be more than one: SOD is suspected of being able to spread from one cell to another (this work will be discussed in detail by delegates in Session 8A: Mechanisms of Intercellular Propagation  on Saturday) but the suspect covered in this session was TDP-43, which shows some structural properties similar to prion proteins.

There are close pathological and genetic links between MND and some forms of frontotemporal dementia (FTD) with a proportion of FTD patients going on to develop MND symptoms. Prof Bill Seeley (University of California) has looked at the part of the brain where the upper motor neurons are found, in FTD patients, and sees the early signs of cellular clumping of TDP-43 protein – the classic pathological hallmarks of MND. He demonstrated using MRI scans of FTD patients, that the spread of pathology from one affected brain area to another may be linked to the connection between these brain regions. In other words, ‘what’s wired together dies together’.

The hope is that if the process of cell-to-cell disease transmission can be understood, then treatment strategies to stop it could mean that the spread of disease symptoms can be slowed. Who knows – if combined with faster and earlier diagnosis, perhaps symptoms could even be localised to the originating part of the body?

The BMAA story in a nutshell

Research into the neurodegenerative condition known as Guam ALS-Parkinson Dementia Complex (ALS-PDC) has tended to find itself slightly isolated from the mainstream MND/ALS research world (‘isolated’ being a good word given that the location of the island itself) but I’ve had an interest since I was first introduced to the subject as a PhD student a quarter of a century ago.

This topic was raised once again on day one of the International Symposium on ALS/MND.

Guam map

So where exactly is Guam?

The Guam Story…

For those of you not familiar with this fascinating and convoluted story, the science writer Wendee Holtcamp has written an excellent article on the subject but in a nutshell (an ‘in joke’ for those who know the Guam story) the basis of the hypothesis is that a toxic molecule called BMAA (beta Methylamino-L-alanine) is produced by certain forms of blue-green algae. The theory goes that the residents of Guam for a while were exposed to higher than usual levels through their diet, which led to a high incidence of ALS-PDC on Guam in the 1950s and 1960s.

Taking the theory further, if high levels of BMAA can cause a neurodegenerative syndrome that includes ALS/MND symptoms and pathology, perhaps lower levels of BMAA might act as a subtle predisposing factor for ALS/MND in other parts of the world?

Is there any evidence for this?

The evidence comes from a broad range of sources: there are several epidemiological studies that suggest that the incidence of ALS/MND is higher in areas of coastline and around lakes (where algal blooms will occur) and indeed, BMAA can be measured in the water in those areas.

We also know, from laboratory studies, that BMAA is toxic to neurons – be it cells grown in culture or studies in animals. A pivotal piece of evidence was performed almost 30 years ago, where BMAA rapidly produced severe and wide-ranging neurotoxic effects in lab models. The doses used were particularly high, so there has always been a question as to whether longer exposure to lower doses over longer periods could produce changes more reminiscent of the ALS/MND and dementia seen in humans.

New results were presented on the first day of the Symposium by Dr Paul Cox (Jackson Hole, Wyoming) validating and extending the original research findings. Unfortunately the results are currently under press embargo until the paper is published, but we’ll provide further details when we can.

The small but highly collaborative ALS-PDC research community also held a satellite workshop later that evening. As everyone in the room was familiar with the background story, the program was in the format of a ‘data blast’, with 14 presenters who were given no more than 10 minutes to update everyone on the key points of their latest findings – no waffle, just the facts! Themes covered ranged though epidemiology (from the Arabian gulf, to France, to North America) analytical chemistry (improving ways of measuring BMAA) neuropathology, molecular biology and pharmacology.

The final presentation of the meeting, by Dr Bob Miller (San Francisco) summarised a pilot Phase 1 clinical study of L-serine (an amino acid that can disrupt the action of BMAA) showing that the compound was safe and well tolerated in patients. Dr Miller also highlighted plans for a larger Phase 2 study to be initiated in the USA in 2016. We look forward to hearing more!

Read about the prequel to this latest chapter on the Guam story and blue-green algae in other posts on our research blog: What’s blue-green algae got to do with it? and Guam story discussion at 2011 ALS/MND Symposium.

Season of mists and mellow fruitfulness…..and prizes….

The fantastic news that Patrick Joyce and his co-inventors have won the 2015 Hackaday Prize for their ‘Eyedrivomatic’ invention is one of a number of research prizes announced this autumn.

Martin Turner award

Prof Martin Turner receiving his award from Prof Jane Dacre, RCP President

At the beginning of November Prof Martin Turner was presented with the Graham Bull Prize for Clinical Science by the Royal College of Physicians (RCP). The Prize is awarded to a member of the RCP under the age of 45 who has made a major contribution to clinical science.

The winner of the Graham Bull Prize is also invited to deliver the prestigious Goulstonian Lecture, an annual lecture given by a young RCP member that dates back to 1635 and the list of previous speakers reads as a ‘Who’s Who’ of the history of British Medicine!

Those of you who know Martin, in particular the many participants who volunteer for his BioMOx research programme will be pleased to see his new title: he was awarded the title of Professor by the University of Oxford in July this year. Aren’t Professors getting younger looking these days…!

Looking north, the pioneering work of Prof Richard Ribchester at the University of Edinburgh has been recognised through winning the Delsys Prize for Innovation in Electromyography. Funded by the MND Association, Prof Richester, Dr Rosalind Brown and colleagues have been developing a novel approach to examine changes to the connections between motor neurons and muscles as the disease progresses.


Prof Richard Ribchester


Prof Ribchester’s work was selected from a field of 75 entries from 26 countries, spanning diverse areas such as biomechanics, robotics, kinesiology, speech pathology and imaging, across the fields of biomedicine and bioengineering.



Further north still, Association-funded investigator Dr Gareth Miles of the University of St Andrews, was recently announced as the recipient of the 2015 Instituto Paulo Gontijo (IPG) Award for Medicine. This annual prize is given to a young investigator who has made an outstanding contribution to the understanding of amyotrophic lateral sclerosis and other motor neuron diseases and in a small number of years has become one of the most prestigious awards in the MND research world.

Dr Miles was judged the winner from a very strong field for his work on characterising changes in human motor neurons created from skin cells of people with MND using induced pluripotent stem cell technology. Dr Miles and his team have identified subtle changes in the electrical properties of these motor neurons that appear to be associated with the disease and which may provide new approaches to treatment in the future. Dr Miles will be presented with his award in the Opening Session at the 26th International Symposium on ALS/MND on 11th December.

Gareth Miles and team

Dr Gareth Miles (centre right) and team

Of course, the ultimate prize – a cure for MND – still eludes us, but these awards do reflect the increasing prominence of MND research across the scientific world as well as the quality of both the research and the researchers whose work we fund.

ProGas study results on gastrostomy in MND published

Under the leadership of Dr Christopher McDermott, based at the Sheffield Institute for Translational Neuroscience (SITraN), research published today on 29 May 2015 in the Lancet Neurology highlights that better weight management in MND is key to survival.

Following on from initial results presented at the 25th International Symposium on ALS/MND in December 2014, the Prospective Gastrostomy (ProGas) study in MND aimed to investigate the optimal timing for gastrostomy in MND due to the lack of evidence available.

Dr Chris McDermott (Sheffield Institute for Translational Neuroscience, University of Sheffield)

Dr Chris McDermott (Sheffield Institute for Translational Neuroscience, University of Sheffield)

Continue reading

Understanding more about GM604

20141020_MND Kings College_290The MND Association’s Director of Research, Brian Dickie explains more about ‘GM6’, also known as ‘GM604’, a drug in development by an American pharmaceutical company Genervon.

The Association funds a wide range of research that leads to new understanding and treatments, which may one day, bring us closer to a cure for MND. We are hopeful that the increasing international research effort into the disease will accelerate the development of an effective treatment for MND. However for non scientists I also fully appreciate how the ‘system’ often seems designed to impede rather than assist this process.

There has been much discussion online about the results of a small scale study of a drug called GM604, or GM6, produced by the American pharmaceutical company Genervon. You can read some general comments about the drug on our website. I’ve written this blog to explain in a little more detail why the research community is cautious about the results. Continue reading

Researchers identify the TBK1 gene as a risk factor in MND

recyclePublished on 19 February 2015 in the Journal Science, an international team of scientists have found mutations in the gene TBK1 as a contributory risk factor in MND.

Identifying TBK1

The majority of cases of MND are caused by a combination of subtle genetic, environmental and lifestyle factors. These subtle genetic factors in the majority of cases of MND (sometimes known as susceptibility genes) may increase someone’s risk of developing MND, but they do not solely cause the disease (they must be present in combination with a number of other factors in order to tip the balance for someone to develop MND). Find out more here.

Under the leadership of Dr Goldstein, based at Columbia University, the researchers have identified a new MND susceptibility gene – TBK1.  The researchers used whole genome sequencing to sequence the entire DNA of over 2,874 MND samples in America – you can find out more about this technique here. By screening a large number of samples, the researchers identified mutations in the TBK1 gene as a common subtle genetic factor involved in some cases of MND in America. Continue reading

SOD1 Stuff

With all the talk of new gene discoveries in recent years, the Sunday morning scientific session returned to the original discovery in 1993 that mutations in the SOD1 gene were responsible for around a fifth of familial (inherited) MND cases and 2-3% of all cases of the disease.

Although much of our understanding of MND in the past two decades comes from SOD1 laboratory models of the disease, we still don’t know exactly how SOD1 kills motor neurons. But that hasn’t stopped several groups from working on a number of innovative ways of protecting motor neurons from SOD1 toxicity. Although focused on a relatively rare form of MND, some of the strategies being followed could potentially also be applicable to other forms of the disease.

sod1 stucture Continue reading

MND Association joins as a Founding Partner of the Neurodegeneration Medicines Acceleration Program

MRCTEver since the G8 summit on Dementia less than a year ago there has been a huge upsurge in international research activity in the field. In the UK, our friends at MRC Technology (an independent medical research charity which aims to bridge the gap between fundamental research and clinical application) were instrumental in forming a Dementia Consortium to aid drug discovery and help charities, universities and drug companies to work more closely together.

Earlier this year, the MND Association and ALS Association met with MRCT to discuss the possibility of extending the collaborative model across other neurodegenerative diseases such as MND and Parkinson’s disease.  This idea has generated a lot of enthusiasm from charities and patient organisations on both sides of the Atlantic, which has resulted in the launch of the Neurodegeneration Medicines Acceleration Program at the Partnering for Cures conference in New York. Find out more about this here. Continue reading