Cogane produces encouraging results in MND Association-funded study

Prof Linda Greensmith
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.

Chromosome 9 finally reveals its secrets

It’s taken a huge international collaboration, including 3 MND Association-funded scientists, to discover a genetic mistake that appears to cause almost 40% of cases of familial (inherited) MND – that’s nearly twice as many as are caused by mutations in the SOD1 gene and more than three times as many as are caused by TDP-43 and FUS combined. Yet despite the fact that it’s relatively common, the rogue gene proved especially difficult to find.

Digging for genes

Our genetic code is arranged into 23 pairs of subunits called chromosomes. Earlier work had homed in on an area on chromosome 9 that appeared to be significantly associated with both MND and the related neurodegenerative disease frontotemporal dementia (FTD), but nobody could drill down as far as the problem gene itself. As a result, chromosome 9 became something of an ‘archaeological dig site’ for MND researchers, with several groups using cutting edge techniques to try and excavate the elusive causative gene that they knew was lurking somewhere in the short arm of this chromosome. The successful international team, which included almost 60 scientists at 37 institutes, finally discovered the exact location and nature of the aberrant genetic code by looking in the most unlikely of places – in the stretches of DNA that do not actually provide any instructions for building proteins, otherwise known as non-coding DNA.

What did the researchers unearth?

The research team studied DNA samples from a Welsh family affected by inherited MND and FTD that was already known to be associated with chromosome 9, as well as samples from a similar Dutch family and a large number of Finnish inherited and non-inherited MND cases. In among the non-coding DNA in a chromosome 9 gene called C9ORF72, the researchers found a 6-letter genetic ‘word’ which, in healthy individuals, is consecutively repeated up to about 20 times. However, in the Welsh and Dutch families and a large proportion of the Finnish familial cases, the 6-letter word was repeated as many as 250 times. This phenomenon is known as a ‘repeat expansion’. The researchers went on to check for this repeat expansion in familial MND cases from North America, Germany and Italy, and found it cropped up in 38% of them. They even found it in a much smaller proportion of sporadic cases from Finland, suggesting that it could be an important risk factor in at least some people with the  non-inherited form of the disease.

What does the discovery mean for MND research?

Despite the fact that the repeat expansion does not directly affect the instructions for building a protein, there is good reason to believe that it can still lead to significant neuronal damage. At the moment it is not fully understood how this happens, but one possibility is that it leads to the production of excessive and consequently toxic quantities of RNA, the molecule that provides the cell with a more usable copy of DNA. Disruption to RNA processing has already been implicated as a disease mechanism in MND – this is the pathway through which faulty TDP-43 and FUS are thought to exert their effects – so C9ORF72 may provide scientists with another piece of the RNA jigsaw.

The effect of the repeat expansion is clearly open to influence. Among those people with the repeat expansion, some experienced only FTD, others showed only muscle weakness, and some had both MND and FTD.  The reasons for this variation in symptoms will be just one area that scientists will now want to look into. This overlap between MND and FTD is something that researchers are very keen to understand, and the C9ORF72 discovery may be the key to solving this puzzle. They will also want to better understand how the repeat expansion causes damage, and that will include trying to find out what C9ORF72 actually does – at the moment this is unknown. (Maybe it’ll get a more interesting name along the way!) Building on the new finding in this way could help move us closer to an effective treatment.

For now, a more tangible consequence of the discovery could be a genetic test for people already diagnosed with familial MND who want to understand more about the basis of their disease. Such a test will take a little time to develop but should become available in the UK in the next few months. When it does, it will be accessible to genetics labs across the country. Anyone interested should speak to their doctor or specialist nurse.  

Dead heat

Just as archaeologists might question whether a newly discovered artefact is the real thing, so scientists need double-checking when they claim to have made a new discovery. Fortunately, a second team hit upon C9ORF72 at exactly the same time, and their results will be published alongside the work described here, in the journal ‘Neuron’. The race to the ‘Lost Ark’ of chromosome 9 ended in a tie, but has provided the research community with a major piece of the MND puzzle on which to build future discoveries.

Article: Renton A, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron (2011).

Read our press release on the C9ORF72 story.

Pointing the finger towards the causes of MND

Would it ever cross your mind that the relative lengths of your fingers might be related to the durability of your motor neurones? Probably not – at first glance the link seems extraordinarily tenuous! However, a research group led Prof Ammar Al-Chalabi, who has close connections with the Association, has found that people with MND tend to have relatively long ring fingers.

So what? Well the results of this study, published this week, do in fact provide some important clues about events occurring before a person is even born that might predispose them to getting MND. For both men and women, exposure to relatively high testosterone levels during development in the womb is associated with having a relatively long ring finger compared to index finger in adulthood. Research has already indicated that testosterone might influence motor neurone health, and increased testosterone exposure in the womb is also linked to male sex and athletic prowess, both of which may be connected with a slightly higher risk of MND.

Prof Al-Chalabi’s team therefore took an extremely simple but ingenious approach to finding out that men and women exposed to higher levels of testosterone during their development as a foetus might be more likely to get MND as adults. Although their results will need confirming in larger studies, they are a reminder of how very subtle factors that might start accumulating before a person is even born, let alone during their childhood or early adulthood, can start to tip the balance towards the development of MND in middle age or later.

Most people with MND are likely to ask themselves ‘Why me?’ and it’s very tempting to look for answers in events immediately preceding diagnosis. The results of this study support the idea that some risk factors may have occurred well before a person could possibly have any memory of them!

More information on what this study means for MND research and people affected by the disease is available in our press release.

Download the official lay article from the BMJ

Article reference: Vivekananda U, Manjalay Z-R, Ganesalingam J et al. Low index-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronal vulnerability. Online First J Neurol Neurosurg Psychiatry 2011; doi:10.1136/jnnp.2010.237412

Collaboration between cancer and MND researchers produces exciting results

It’s been a busy couple of weeks for exciting research results! Hot on the heels of the publication of Dr Turner’s imaging study, MND Association-funded researchers who pioneered a state-of the art technique adapted from cancer research have just published results describing some of the earliest events in MND-related degeneration.

Prof Giampietro Schiavo and colleagues at Cancer Research UK worked with Prof Linda Greensmith, an experienced MND researcher at University College London, to modify a process known as ‘multiphoton microscopy’, which had previously been used to visualize the migration of cancer cells. This allowed them to watch important ‘cargo’ being transported around motor neurones.

In their report published this week in the journal PNAS, the researchers have described how the transport of nerve-nourishing substances from the end of the neurone where it connects to the muscle back up towards the neurone’s ‘control centre’ in the spinal cord is slowed at the very earliest stages of MND. This suggests that transport systems could be a key target for drug development. Further details on the research are available on our website.

A key element of our strategy is to increase the capacity of the MND research workforce. Encouraging experts from other fields to collaborate with established MND researchers is one way of achieving this so we are really pleased to see the alliance between Profs Schiavo and Greensmith bear fruit. This is a great example of ‘thinking outside the box’ to progress MND research and the cross-fertilisation of knowledge and ideas between scientists working in different research areas.

Reference: Bilsland LG, Sahai E, Kelly G et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A. 2010 Nov 8. [Epub ahead of print] doi:10.1073/pnas.1006869107

Three new projects, three steps closer to a world free of MND

Next month will see the start of three new Association-funded research projects that will each move us closer to achieving some of the key targets set out in our research strategy. They involve recently discovered genetic causes of MND, new disease models and a novel way of measuring the progress of the disease – all very exciting stuff! You can read more about the projects here.

The three research teams involved are embarking on their new investigations just as Marion and Natasha are busy preparing for next month’s Research Advisory Panel meeting, where more applications for funding will be assessed. The MND research machine never sleeps!

Information means informed choice

Alternative treatments can be tempting if you have a disease like MND, for which conventional medicine can only offer one moderately effective drug.  Unfortunately this temptation is easily preyed upon by clinics around the world that claim to be able to provide effective treatments or even a cure (at great expense of course), despite having no supporting evidence.

We often take enquiries from people with MND who are considering undertaking one of these ‘unproven’ treatments and want to know if we have more information about them. Often, all we can talk about is the lack of sound evidence that they work, so it can be helpful when a bit of hard evidence does come along – even if it’s suggesting that the treatment doesn’t work. This is the case with an article from the journal ‘Brian Pathology’, which crossed my desk recently.

Many people with MND have travelled to a clinic in Beijing to receive a type of stem cell treatment  known as ‘olfactory ensheathing cell (OEC) transplantation’. This treatment is effectively experimental, having not undergone clinical trials, yet the Chinese clinic demands large sums of money from its patients and does not appear to follow their progress after treatment.

Independent neurologists who have tracked the progress of people with MND before and after treatment in China have failed to see any real improvement in their condition. Now, Italian scientists have presented in Brain Pathology some clues as to why this treatment isn’t working.

Two Italians with MND who had undergone the Chinese treatment generously donated their brains for use in research after they had passed away. This gave the scientists an opportunity to look at what had happened to the transplanted stem cells. They were able to see the tracks left by the needles used during the procedure and found that all of the tracks ended in different places, with none of them actually reaching the main motor neurone pathway from the brain to the spinal cord. The researchers did find some OECs, but they had been trapped within the needle tracks by the brain’s own defence mechanism – so the stem cells never got to where they were really needed.  In addition there was no sign that the transplanted cells had produced any neurone-nourishing substances or turned into neurones or support cells – all mechanisms by which stem cells could potentially have some effect in MND. In light of all of this, it is not surprising that the researchers also found that brains showed all the typical hallmarks of MND degeneration and that their donors had experienced a typical progression of their disease.

This research may only have looked at the brains of two people with MND, but it all adds to the information we can give people who ask us about this treatment – and information means informed choice.

Kate – incurable optimist

When I started my job at the Association just four years ago we were funding 19 research projects and studentships. Researchers were using animal models based on the one major disease-causing gene that had been discovered to try and learn more about the mechanisms underlying all types of MND, which I thought was all pretty clever and promising.

Today, the Association is funding 45 projects including Clinical Research Fellowships that will help develop the careers of the very best young clinician scientists. A flurry of recent gene discoveries has provided researchers with significant clues and opened up completely new avenues of investigation, whilst stem cells have become a realistic tool for enabling scientists to study living human motor neurones in the lab. That’s a lot of progress in four years. Research always moves forward.

It gets cleverer and more promising all the time – that’s why I’m optimistic.

Follow our incurable optimism campaign

Time to play the guessing game!

 

As the abstract submission deadline for the International Symposium draws nearer (3 May), everyone in the team likes to have a stab at guessing how many abstracts we’ll end up with.  For most of us this involves taking last year’s final number and increasing it by a bit to account for the symposium’s ever-growing reputation and standing as the world’s premier MND research conference.

However for Kelly, our resident statistics boffin, there is a meticulous method involving averages, graphs and a careful analysis of the trends over the last few years… 

Anyway, we’d love you to have a guess too. To give you some idea, last year we ended up with just over 400 abstracts and the team guesses range from 220 to 470!

We will check the final number of abstracts submitted on the morning of 4 May and until then we will wait with anticipation and hope that the number of abstracts soar from 45 to their hundreds over the weekend!

The calm before the storm

MND researchers from around the world who are hoping to present their work at this year’s International Symposium on ALS/MND are (we hope!) preparing to submit to us brief summaries of their proposed presentations.

These summaries, known as abstracts, have been trickling in since March. Based on the form of earlier years, the trickle will become a tsunami in the last 48 hours before the 3 May deadline – the numbers are likely to leap up from the twenties into the several hundreds. Researchers like to cut it fine!

Meanwhile, the research development team waits with bated breath. It’s hard to organise a stimulating symposium programme from just 26 abstracts but we have faith that the international research community will come up trumps!

Spring conference reflections

This weekend the Association held its first regional Spring Conferences for 2010 and I was lucky enough to attend Saturday’s conference in Newport. I really enjoy spring conferences – it’s great to be able to talk face to face with people affected by MND and the Association’s fantastic volunteers. Quite a few Association Visitors visited our research stand to chat about topics including the rare, inherited form of MND and the appearance of ‘clusters’, where it seems as if several people in a small area have the disease (you can read more about this on the ‘Why me?’ page of our website). I hope they went away feeling that I’d armed them with some new and useful information!

The conference was also a good opportunity to hear about the successes and plans of other teams. The talk from Steve Bell, our director of regional care for the north, provoked some good questions about the Association’s plans for improving services for people with MND. Later in the day during the session led by our Policy and Strategy Unit, everybody got stuck in and practised putting canvassing MPs on the spot about the National Strategy for MND – parliamentary candidates beware! You can read more about the call for a National Strategy and sign our petition at www.mnd2010.org .

Throughout the day the room buzzed with lively chatter during breaks as people shared their experiences and made new contacts – exactly what these conferences are all about!

There are three spring conferences left this year in Harrogate, Blackpool and Cheshunt – all of which will be held in May. If you’re interested in attending, or want to find out more about what they are all about then please visit our spring conferences section of our website.