Prof Linda Greensmith

Thanks to funding and some strategic ‘match-making’ by the MND Association, a new drug may have taken one step closer to beginning clinical trials in MND after producing promising results in an animal model of the disease.

The drug, known as Cogane, was developed by the biotechnology company Phytopharm. It had already demonstrated in laboratory tests that it could help to protect neurones by promoting the production of natural, nerve nourishing substances called neurotrophic factors and early animal testing had hinted at its potential beneficial effects in MND. However, its journey towards clinical testing in MND had hit a road block because it hadn’t been extensively put through its paces in large numbers of the most widely used animal model of the disease, the SOD1 mouse. Without robust data from this model, there would have been little to encourage further investment in Cogane’s development.

So up stepped the Association to introduce Phytopharm to Professor Linda Greensmith at University College London, a leading MND researcher with considerable expertise in SOD1 mouse testing. With funding from the Association, Prof Greensmith and her team were able to conduct a rigorous study of the effects of Cogane, administered to the mice after they had developed MND-like symptoms.

The drug produced some significant improvements in muscle strength and motor neurone survival and managed to produce positive effects even in mice that had reached the later stages of the disease. To give more substance to these preliminary but very encouraging results, the research team will now go on to the painstaking work of examining more closely Cogane’s effects on the motor neurones and other key cells that play a critical role in the progression of MND. 

After the disappointment of the Trophos trial results, it’s great to be able to share some positive news on the drug development front. We know from long experience that it’s wise to limit our excitement over positive results from the mouse model – after all, plenty of drugs have shown promise at this stage and have then gone on to fail in clinical trials. However, Prof Greensmith’s experience and expertise mean that Cogane will have been tested with the utmost rigor. As she herself commented, the results indicate that “Cogane has significant potential as a therapy for ALS and merits further evaluation”.  We don’t yet know what Phytopharm’s next steps will be – these may become clearer once the more detailed data from Prof Greensmith’s work have been published, which could take the best part of a year. Let’s hope that we have a given Cogane enough of a boost to push it out of the drug development ‘doldrums’.

Read the Phytopharm press release.

Our DNA bank contains over 3,400 samples from people with MND and their families.  By using these samples scientists in this country have already made significant discoveries into the causes of MND. To advance research into MND we now want to make the DNA bank available to researchers across the world. To do this, we’re asking people to donate funds to the BBC Radio 4 charity appeal for our DNA bank. All money raised through the appeal will go towards maintaining the samples and making them accessible to worldwide researchers. It will take a global research effort to beat MND, and the DNA bank is a very important tool in the fight against the disease.

Samples from the DNA bank will help scientists identify genes that cause familial (inherited) MND or those that influence susceptibility to sporadic MND. This will offer crucial insight into the causes of MND. Understanding the causes of MND will lead to the development of new treatments.

To listen to the broadcast narrated by Joss Ackland, listen in on Sunday 8 January at 7:55am or 9:26pm to BBC Radio 4. This will also be repeated on Thursday 12 January at 3:27pm, or you can listen again after the broadcast.

More information:
DNA bank samples are currently being used in a number of studies investigating the causes of familial and sporadic MND. For more information, please see the DNA bank pages of our website.

If you contributed a sample to our DNA bank, you can find out more about what happens to samples after they’re donated in our information sheet, and in our Thumb Print article from 2010.

Read our press release on this story.

1. How many neurones does a human have? Billions
2. Which animal has the largest brain? Bottlenose dolphin
3. How much does a human brain weigh in comparison with our total average body weight (in percent)? 2
4. How many DNA samples does the MND Association’s DNA bank hold? 3,400
5. How many research projects do we currently fund? 44
6. How much does our research project portfolio currently come to? £7.6m
7. How many PhD studentships do we currently fund? 12
8. How many times a year do we have research grant funding rounds? 2
9. How many unproven MND treatments have ALSUntangled investigated so far? 13
10. How many stem cell research projects do we fund? 2

At the beginning of a new year, it’s always encouraging to look back on how far we’ve come. The list of MND research achievements continues to grow exponentially every year, and I’m pleased to say that last year was no exception, demonstrating that we really are living in exciting times.

2011 had some important discoveries in the world of MND research to find the answers to what causes MND. A number of MND causing gene mistakes were discovered including C9ORF72, Ubiquilin2 and SQSTM1. With these findings, we now know the cause of approximately 70% of cases of inherited MND – a massive leap from approximately 25-30% of known genetic mistakes the previous year.

Within the team, we’ve also made some promising headway toward our aims set out in our research strategy, by funding and promoting cutting edge research both within the UK and around the world. For example, our groundbreaking biomarker project led by Dr Martin Turner at Oxford yielded its second set of promising results, just three years into the five-year project. Dr Martin Turner also gave an enthralling talk at last year’s International Symposium on ALS/MND on neuroimaging (brain scanning) and he’s regarded as ‘the man’ to speak to in terms of MND neuroimaging on an international level.

As well as the research projects that we fund yielding positive results, and following progress on an international level, we’re also a major player in promoting research. The key to defeating MND lies in fostering strong collaboration between leading researchers around the world  and sharing new understanding of the disease as rapidly as possible. In 2011, we made two huge steps in this:

In January 2011, in conjunction with two leading members of the International Consortium of Stem Cell Networks (the Canadian Stem Cell Network and the UK Stem Cell Network), The New York Stem Cell Foundation and the ALS Association of the USA, we organised an MND stem cell conference. Our workshop brought together 60 of the world’s leading stem cell research experts to shape the development of future international MND stem cell research and to form new research collaborations. We were privileged to organise this event and the research community now have a solid foundation of understanding of where we are in terms of MND stem cell research. Dr Brian Dickie, our Director of Research now also has the honour of being a co-author on the scientific paper from the conference – published in the journal ALS.

In July 2011, we made a further step forward in sharing new understanding rapidly by joining a group of research-funding organisations to fund UK PubMed Central, an online research database containing over two million research articles. This is the first step in the Association’s aim to establish a comprehensive resource for the global MND research community.

We also had a fantastic year for improving the way we fund research and maintaining our high standards.

For our first grants round of the year, a record-breaking 19 full applications were considered for funding by our Biomedical Research Advisory Panel. Only one in five research applications is considered of a high enough standard for funding, but through our rigorous process we can provide our donors with the assurance that they are supporting the ‘very best of the best’ MND research.

Before our second grants round, we announced the successful launch of our online summary application form for researchers applying for grants and PhD studentships. By evolving our summary application process to use an online system, we are able to ensure that our high standards are maintained and that we are using our time efficiently and effectively to fund high-quality research.

We also proudly received our certificate for best practice for our rigorous procedures for funding research from the Association of Medical Research Charities (AMRC) in the UK with a comment saying that we are “considered as setting the standard within the audit”.

You can find out more information on the research projects we currently fund on our research we fund information sheet.

One of our highlights from last year, and the result of over a year’s work in preparation from the research team and our conference team, was the International Symposium on ALS/MND held in Sydney, Australia. We are proud to organise this vital worldwide event every year, and are pleased that last year was successful. Holding the event in different countries around the world enables us to draw new people into the international research community, bringing new ideas and expertise to the field and creating new alliances in the fight against MND.

We took you behind the scenes of last year’s symposium by writing daily blog articles on a multitude of topics. If you’ve not already read these, you can find an introduction to these with links on our blog. Please remember to complete our survey on what you thought of our reporting, as it really helps us to determine whether we should continue to report from the symposium, and whether we should change anything.

We’ve definitely set the bar in 2011 and have a lot to live up to in 2012. We’re really looking forward to see what 2012 holds for MND research, and we hope that you’ll continue to follow our progress on our blog throughout the year.

We wish you a very Happy New Year from all of us in the Research Development Team at the MND Association.

1. How many neurones does a human have? Thousands, Millions or Billions?

2. Which animal has the largest brain? Bottlenose dolphin, Human, or a Walrus?

3. How much does a human brain weigh in comparison with our total average body weight (in percent)? 1,2,5?

4. How many DNA samples does the MND Association’s DNA bank hold? 3,400, 2,300 or 1,200?

5. How many research projects do we currently fund? 44, 88, 102 ?

6. How much does our research project portfolio currently come to? £2.3m, £7.6m, £10.8m?

7. How many PhD studentships do we currently fund? 12, 18, 25

8. How many times a year do we have research grant funding rounds? 1, 2 or 3?

9. How many unproven MND treatments have ALSUntangled investigated so far? 5, 9, 13?

10. How many stem cell research projects do we fund? 0, 2, 5?

Good luck and have a Happy Christmas!

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.

Listening to his presentation I got the gist of the overall positive message – a real step forward in MND research – but to report in any more detail of how and why was a step too far for my brain when I was in Sydney! Reading through my notes when I got back to the office, I was determined to get to the bottom of this science. It helped me to write a non-technical summary of it as I went. It’s perhaps a bit more technical than our normal blog posts – but I couldn’t resist the opportunity to (try and) share my new found knowledge. So here goes:

Inflammation is one response of the immune system. The immune system is a community of cells that exist within your body to protect it from damage and to maintain its status quo. Given its important function, it is perhaps reassuring to know that how it works is mind-blowingly complex!

In the brain and spinal cord, a slightly different defence system exists in comparison to the rest of the body. It is now common knowledge that motor neurones are surrounded by cells that support their function – known as glial cells. Within the community of these glial cells there are ‘police’ cells called microglia. Prof Appel’s lab has contributed many elegant studies to a consensus of research showing that in MND these police cells operate a delicate balance between protecting the environment around motor neurones and triggering a toxic atmosphere. Gradually the toxic atmosphere prevails.

In Sydney, Prof Appel discussed another component of this defence system, ‘regulator T-cells’. Continuing the police analogy, T-cells patrol the blood, rather than the brain and spinal cord tissue of microglia. As their name suggests, regulator T cells regulate the response rate of removing toxins and maintaining a healthy environment, in particular they regulate microglia by sending out specific chemical signals.

Prof Appel wanted to know how the interaction of T-cells with microglia is affected in MND. He found that a large ‘police presence’ (or high numbers) of regulator T-cells influence microglia to maintain their protection of motor neurones. In other words, large numbers of regulator T-cells kept motor neurone death at low level, showing itself as a slower phase of disease progression. As the levels of regulator T-cells get lower, the microglia turn toxic and the rate of progression of the disease speeds up. These conclusions were based on studies in mice models of MND and in patients at different stages of MND – by analysing blood samples for the presence of regulator T-cells and comparing this with what they knew of their symptoms.

This information presents two opportunities to MND researchers – firstly if therapies can be developed to maintain the levels of these regulator T-cells they may slow down the disease; and in the meantime, chemical markers in the blood, used in these studies, may be a valuable biomarker to measure the rate of progression.

Word cloud from our symposium reporting in 2011, creating on wordle.net

We organise the International Symposium on ALS/MND every year, and it is regarded as the premier medical conference on MND and a highlight of the research calendar.  In 2011, the symposium was held in Sydney Australia where 650 researchers, clinicians and healthcare professionals  from 33 countries met to discuss recent advances in MND research and care from around the world.

To give you a taste for what the symposium is all about, and tell you what the findings that were being discussed really meant, we wrote over 8,000 words in our daily articles on this blog.

After you’ve finished reading the symposium articles that interest you, we’d be grateful if you could spare a few minutes to fill in our short online survey on our symposium reporting. Your comments really are useful and allow us to continually improve our symposium reporting: http://surveymonkey.com/s/mndresearch

Here’s a brief guide along with links for the full articles:

Rip roaring start to the symposium
Being welcomed by Glen Doyle on behalf of the Gadigal tribe of Australia was a stunning start to the symposium. This was followed by a spectacular explanation using ping pong balls and rat traps to explain how all forms of MND need a trigger.

Copying, transporting and creating proteins – what could possibly go wrong?
TDP-43, a protein which can cause MND, is normally involved in editing or reading up to one third of all proteins within the cell – now that’s a city fat cat type of job!

Mediating the delicate balance between protection and damage
The speed of progression in MND appears to be dictated by the delicate balance between protection and damage of the ‘innate’ immune cells in the nervous system. Could tilting the balance back to protection be a good therapeutic strategy?

If you were a car, would you be a Ferrari or a Focus?
People with MND may well come from among the Ferrari’s of the human race…

A quick peruse of the posters
An update on the Neuralstem stem cell clinical trial and answering whether riluzole has an effect on a drug that is currently being trialled called dexpramipexole.

Next chapter of BMAA detective story
A tale that has been woven for the past 60 years including an exotic island, bat eating natives, and how researchers are striving to work together to solve this mystery.

Beauty and the beast – when misfolded proteins cause havoc
Tale as old as time… find out how and why proteins can become disfigured into ‘beasts’ to cause MND.

The season of the gene
Researchers are beginning to look to genetics in a new way. It seems that there is a huge potential to make discoveries and connections a lot faster.

Windows to the brain
Brain scanning technology reveals that people with MND have different levels of brain activity than those without the disease. This study demonstrates another step forward toward a clinical test for MND.

Clinical trials low down, down under
Recent clinical trial findings were discussed including the Dutch lithium trial, memantine trial, Nogo-A (GSK) trial and biomarker findings from the first phase of the NP001 trial.

Changing fashions of MND models
Stem cells are not the panacea of models, they’re an arrow in a quiver of techniques…

The 23rd International Symposium on ALS/MND will be held in Chicago, USA on 5-7 December 2012.

So in some ways it was quite a relief to walk into the final session of the meeting this afternoon, but in other ways quite sad too. Dr Bryan Traynor from the National Institute for Health in the USA gave a concise, accessible and comprehensive overview of the ground breaking discovery of the C9orf72. It was good to hear the detective story of how he and his colleagues came to actually make the discovery, the analogy of gradually narrowing down the area of DNA to look in from a city the size of Sydney, to a long street to eventually to a small one-road-through-not-very-googable village was much appreciated. (It also manage to increase the species of analogy animals mentioned at the meeting to cows – not one that I’d heard mentioned until then).

For me however, the highlight of this session was Prof Kevin Talbot’s concluding presentation on ‘Where to from here’. It was an articulate summary of what the whole MND research community has been told, discussed and digested over the three day conference and suggested some pointers of where we should go next.

That’s me done until I get back to home!

Please don’t forget to complete the survey for us on the reports from the meeting – it really does help. My grateful thanks to Kelly and Kate back in the office for all their preparatory work for these posts, it was a team effort.

Read our official press release from day three of the symposium.

A number of key developments both in terms of technological know-how and new understanding of genetics of MND have led to the development of new models discussed at on the last day of the symposium.

Stem cells
The session was opened with a presentation on what is arguably the most glittering and exciting of these new models, that of using so called ‘iPS’ cells. The principle behind iPS cells (induced pluripotent stem cells to give them their full name), is that it’s possible to take a skin cell from someone with MND, coax it back into basic stem-cell-like state and then change it into motor neurones. The idea that this was even possible was scientific heresy say five years ago. The beauty of this technique is that you then have living human motor neurones in dish in the laboratory.

Dr Kevin Eggan from Harvard University Massachusetts USA is one of the leading lights in this technology and he treated us to an update of his latest research. “In itself, ALS is an interesting test tube for stem cell research” he said, adding “this is my first ALS meeting, I’ve enjoyed it and learnt a lot”. Aswell as being the first time that it was possible to study the cells directly affected in MND (motor neurones), iPS techniques also allow researchers to study the behaviour of motor neurones at as close to the actual disease conditions as possible.

Are they really motor neurones?
In the first part of this talk Dr Eggan explained and demonstrated that the cells that he and his colleagues have grown really are motor neurone-like and that they do behave like motor neurones. However he did caution that this model is not the panacea of ALS models, it’s an arrow in a quiver of techniques.

How do these motor neurones behave?
The second half of his talk concentrated on whether these human motor neurone models behave differently to motor neurones grown from skin cells of unaffected people.

When given the same growing conditions, motor neurones derived from people with SOD1 mistakes (mutations) were found to be less plentiful when growing ‘in a dish’ than those derived from healthy individuals. The SOD1 motor neurones also display a different pattern of electrical activity (transmitting electrical activity, is, after all, one of the main functions of motor neurones). The next steps of this research will be to double check that the effects seen in cells with SOD1 mutations really are due to this faulty gene and investigate the effects of other known genetic causes of MND in these cells.

Of mice and men
Moving from a new model to an old and arguably less fashionable one, Dr Greg Cox was given the title of “Are mice a good model for human ALS”. His first slide was to turn this question on its head and state that humans are a terrible model for mouse ALS! His point was that there are so many things that are unknown in human MND that generating a truly accurate mouse model for it was an almost impossible task. Saying this, he went on to discuss three key essentials for any mouse model, so called face, construct and predictive validity. Towards the end of his presentation he shared some results of one of this own studies, explaining that there is an area of our genetic code, not identified in MND before, that seems to carry a mistake that causes symptoms of MND.

Read our press release from day three of the symposium.

Your feedback on our symposium reporting means a lot to us, please spare 5-10 minutes to complete our short questionnaire before you leave our blog, thank you.

Designing a good trial
As MND is a rare disease clinical trials are notoriously difficult to design in order to ensure that they have meaningful results. Designing better and quicker clinical trials will aid us to find the answers as to whether a treatment is beneficial or not, without losing the significance of a study. It is therefore important that clinical trial designers share their methods with one another. In the first presentation of this session Prof Miller gave us some pointers on how this may be done, looking at every aspect from designing shorter trials with fewer participants, to how an effect is measured.

The next few talks were then dedicated to discussing results from recent clinical trials:

Lithium
Prof Leonard van den Berg, from University of Utrecht, The Netherlands presented the results from the Netherlands lithium clinical trial. Unfortunately, although they found the treatment to be safe, no beneficial effects were seen. The results from the UK clinical trial of Lithium Carbonate, which was designed in a different way with more participants will be published early 2012.

Memantine
Dr Ming Chan from University of Alberta, Canada discussed the results of the recent memantine pilot trial for MND. This trial treatment was administered via tablets. Twenty four people took part in this study and were randomly divided into one of three groups who would receive either: high dose memantine; low dose memantine; or a placebo (dummy) drug. Overall, the trial results suggested that the treatment is safe, and at the higher dose a larger, multi-centre clinical trial for memantine may be warranted.

Nogo-A (GSK1223249)
Dr Pierre-Francois Pradat from the Centre for MND in Paris, France presented the very hot-off-the-press results of the Nogo A trial – a drug developed by the pharmaceutical company GlaxoSmithKline, that is delivered directly into the blood stream via an intravenous (IV) drip. This was a Phase I ‘first in man’ study, given to people with MND first. This is different to other Phase I clinical trials, as healthy volunteers are more commonly used for this stage of trial.

The aim of this study was to ensure that the treatment was safe and well tolerated in people with MND. Dr Pradat discussed that the drug was found to enter the body effectively. The investigators saw trends (ie they are not statistically sure) of benefits in slower decline of respiratory function, of a scale that measures the functional capabilities of people with MND called the ALS-functional rating scale (ALSFRS) and muscle strength. Tentative plans are underway for a larger clinical trial next year.

NP001
NP001 is a drug developed by Neuraltus Pharmaceuticals.  This trial treatment is administered directly into the bloodstream via an intravenous (IV) drip.

At present a Phase II clinical trial for NP001 is underway in the USA and we acknowledge that a lot of people living with MND are interested in hearing more about the status of this trial. This talk however, focused on the Phase I trial to tell us the effects of NP001 on potential markers of disease progression in MND (known as biomarkers), identified through the earlier Phase I trial. We can therefore not comment on the current status of the Phase II trial in this blog article.

As discussed by Prof Miller, from Forbes Norris ALS/MDA Research Center in San Francisco USA and principle investigator to the trial, it is thought that NP001 may be beneficial as the levels of proteins which are increased as a result of an inflammation response in MND are decreased by the drug. They also concluded that the levels of these inflammatory response proteins can be related to the rate of progression for people with MND and could potentially be used as a marker.

Read our official press release from day three of the symposium.

Your feedback on our symposium reporting means a lot to us, please spare 5-10 minutes to complete our short questionnaire before you leave our blog, thank you.