New urine-based biomarker opens a gate to improved tracking of MND

Researchers from the Flinders University, Australia and University of Miami have discovered a new protein that can act as a biomarker to track disease progression in people with MND. A paper written under the leadership of Dr Shepheard and Dr Rogers was published today in the research journal ‘Neurology’.


What is p75 and what do we know so far

mndassociationgeneral3The biomarker is a protein called p75, which initially
supports the growth of neurones during embryonic development and its levels markedly decrease after birth. Throughout our lives, p75 only reappears in higher levels when the body detects injury of the nervous system, and shows its presence in urine.

The researchers have previously shown that, after birth, mice with a mutation in the SOD1 gene, known to cause MND, had high levels of p75 after about 40 days from the onset of MND. This also coincided with increased levels of p75 in motor neurones found in tissue of people with MND after death.

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Progress in the MND Oxford BioMOx project

MND Association funded researcher Dr Martin Turner at University of Oxford has identified a pattern of degeneration in the brains of people with MND that is linked to the level of disability.

This finding brings us closer to identifying a biomarker that can be used to speed up the diagnosis of MND, which can be delayed on average by a year since first symptoms.

This is the third finding to be announced since Dr Turner was awarded with the MRC/MND Association’s Lady Edith Wolfson Clinical Research Fellowship in 2008.

You can read more about this exciting finding on our website:

Progress in the Oxford BioMOx project | 2013 | MND Association.

Reference: Stagg CJ, Knight S, Talbot K, Jenkinson M, Maudsley AA, Turner MR, Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS. Neurology 2013; DOI 10.1212/WNL.0b013e318281ccec

Why we need biomarkers

Yesterday’s announcement by the biotechnology company Trophos SA of the lack of effectiveness of their compound olesoxime adds to the long list of drugs that have failed to live up to their early promise in the lab.

It’s a story that’s common across the world of neurodegenerative disease, including common conditions such as Parkinson’s disease and Alzheimer’s disease. The path from bench to bedside is fraught with pitfalls….

In their press release, Trophos suggested that trials have to be conducted when the ‘window of opportunity’ is greatest – the sooner a drug is administered the better its effect is likely to be. Otherwise, we don’t know whether these treatments genuinely do not work or is it simply a case of ‘too little, too late’?

Certainly, companies such as Biogen Idec have picked up on this, restricting the time limit for inclusion in their trial of dexpramipexole to two years from symptom onset, as opposed to the three year (and sometime longer) limit that has been used in previous trials. It means that Biogen Idec has to involve more local MND clinics to recruit the numbers needed, for the trial, which increases the cost, but they view this as necessary if they are to increase the chances of a positive result.

Similarly, the way MND manifests and progresses can be so different in one individual compared to the next, meaning that trials need to recruit large numbers of participants to reduce the statistical ‘noise’ – once again increasing the already high cost and complexity of the trial.

We will only make major inroads into earlier diagnosis and more accurate predictions of how the disease will progress if we can identify biomarkers – specific biochemical and/or structural changes that occur within the brain and spinal cord that provide us with a unique ‘fingerprint’ of MND. 

Biomarkers can also be tailored to look at the effects of specific drugs in trials. Even if it is unclear whether a drug is working on the ‘outside’ (on muscle function for example) it would at least be possible to confirm it was working on the ‘inside’ by reaching the right parts of the brain and spine and acting on the correct chemical processes.

In a nutshell, biomarkers would likely lead to smaller, faster and more accurate trials. That would mean trials could be performed more cheaply – and cheaper trials would almost certainly mean more trials.

This is why the MND Association sees biomarker research as so important. We are currently supporting three clinical biomarker projects (in London, Oxford and Sheffield) which are among the most comprehensive examples of this research in the world. Without the commitment and enthusiasm of those who participate, we wouldn’t be able to create these vital research resources which, as highlighted in previous postings, are beginning to generate promising early results.

But these projects are just the start. Their findings will need to be confirmed in much larger studies, involving the collaboration of MND clinics across many countries, collecting clinical data and samples to precise scientific protocols. This was the rationale behind a major biomarker funding initiative announced earlier this year under the European Union Joint Programme in Neurodegenerative Diseases (JPND). Established by 23 European countries, the JPND Research Call invited funding bids to assist the harmonisation of biomarker collections and the development of new methods of analysing the samples.

On Friday, JPND announced the four projects shortlisted on the basis of “scientific excellence” for a share of the €15 million (approx £12.6 million) research fund. One of these projects is SOPHIA (Sampling and biomarker OPtimisation and Harmonisation In ALS).

Co-ordinated by Prof Leonard van den Berg, the SOPHIA initiative will span up to 16 centres across 12 European countries, including the MND Association’s Sheffield and Oxford Care Centres. The precise level of funding has not yet been determined, but nonetheless this provides a fantastic platform on which major international biomarker research can be developed. We will of course keep you posted once the final outcome is known.

Workshop on closer European working

Last weekend 19 neurologists and researchers gathered in a hotel seminar room in The Netherlands to talk about building closer links across Europe.

Prof Leonard van den Berg, the current chair of the European ALS Consortium organised the workshop to work out how we can collaborate more effectively across Europe. Prof van den Berg is a neurologist specialising in MND with a busy and active research group, based in Utrecht in The Netherlands.

Ultimately we would like to have the infrastructure in place so that European researchers can react quickly to new opportunities in MND. For example, what would we want to do if another drug like lithium came along?

 In 2009 a number of clinical trials to investigate whether lithium carbonate may be effective in people with MND were organised and funded on a national basis across Europe. (The UK clinical trial is still ongoing, although closed to recruitment). These trials represented a milestone in MND clinical research. Why? Because they were the first MND trials for many years that did not involve pharmaceutical companies. Crucially as well as providing the drug that may be beneficial, pharmaceutical companies also provide the infrastructure and funding to conduct the studies.

As we know from the example of the UK Department of Health’s Dementias and Neurodegenerative Disease Research Network (DeNDRoN) having an infrastructure already in place greatly enhances our ability to conduct non-pharmaceutical led trials. The support from DeNDRoN includes ways of monitoring the trial while it is in progress and analysing the results when it has finished. The lithium study proved it is possible for neurologists and researchers to co-ordinate their own national clinical trials, the next step will be to work together to co-ordinate European clinical trials.

It was agreed that the first step to develop this infrastructure was ensure that we have more ways of sharing information on current research activities and a greater ability to react quickly to new opportunities. Linked to improved clinical trials is the availability of biomarkers that can be used and measured in a consistent way. Such biomarkers may improve the diagnostic process and therapeutic monitoring in MND. During the workshop a way of sharing the protocols for measuring biomarkers across Europe was agreed.

Delegates attended from the UK, Ireland, France, Germany, The Netherlands, Belgium, Italy, USA, Switzerland and Portugal representing a wealth of expertise: from running clinical trials; designing databases and registries; and developing a range of biomarkers from brain imaging to electrophysiology. As well as talking about improved collaboration, it was a great opportunity to hear about other research activities underway. It was also striking to note how well the proposed activities fit with the Association’s research strategy.

The workshop was organised by the European Neuro Muscular Centre (ENMC), who looked after us very well.