Adaptive licensing and MND

I have recently updated the clinical trials section of our website with a couple of MND clinical trials that are currently recruiting. This has led me to think about the adaptive licensing discussions that have been taking place recently and how this relates to these MND clinical trials.

Adaptive licensing is an idea. An idea that has seen increasing media attention over recent months and years.  Adaptive licensing aims to see the licensing of drugs somewhat earlier than they currently are at present, particularly with regards to those living with diseases like MND. We, the MND Association, therefore encourage further exploration into the idea of adaptive licensing including as to how it may work.

The current situation

In order for a drug to be licensed in the UK it needs to have been shown to be both safe and beneficial by means of a clinical trial. Clinical trials are considered the ‘Gold standard’ for drug testing in humans and consist of four main parts:

• Phase I Testing the safety of a drug for the first time in healthy people
• Phase II Testing the optimal dose, safety and tolerability of a drug in people living with the disease
• Phase III Testing if a drug is effective (beneficial) at treating a larger group of people living with the disease
• Phase IV Testing and monitoring a drug (including side effects) once it has been licensed for use

After phase III testing the drug, and all of its clinical trials data, is reviewed by the appropriate licensing body before the drug can be licensed for use. If a license is given, then data will be continuously collected over a longer period of time, which is known as phase IV testing.

It is important to know that some drugs, which show promise in the lab, are shown not to be effective in a large phase III clinical trial (particularly with diseases like MND). This is why clinical trials are needed. Drugs, which are not beneficial or may have harmless side effects, need to be fully tested so they are not given to people unnecessarily.

These strict guidelines for clinical trials are in place to protect patients and to ensure that people living with MND are not given treatments that may be harmful or offer no benefit. For more information about clinical trials see our information sheet

The adaptive licensing idea

The European Medicines Agency (the European drug licensing body) describes adaptive licensing as a system that, “seeks to maximise the positive impact of new drugs on public health by balancing timely access for patients with the need to provide adequate evolving information on benefits and harms.”

Clinical trials take time and the aims of adaptive licensing are for ‘more drugs to be available to more people and more quickly’ which we heartily agree with.

But, we do not know how an adaptive licensing approach may work. As it is still currently just an ‘idea’ there are lots of questions that need to be answered. Including; who would administer the drug, and how would their effects be monitored? Who would be responsible – the doctor or the drug company? Would there be a ‘control or placebo group’? What would happen to clinical trials?

This is why the Association encourages answers to these questions by further exploration into the ideas of adaptive licensing including as to how it may work.

Read more:

Our campaigns team have written a series of blog posts, which explain more about adaptive licensing and what it means for people living with MND;

• Adaptive licensing and the MND Association’s position An overview of how a model of adaptive licensing might help to get more drugs to people with serious illnesses like MND more quickly.
• Recent developments in legislation and policy This post explores the various policy initiatives, including adaptive licensing, that have been set up to try to get new medicines to patients earlier.
• Challenges of adaptive licensing, and implications for people with MND This post looks at some of the unresolved issues that must be addressed before we know whether adaptive licensing will provide some of the answers we would like to see.

Progress in MND research

Our understanding of MND has progressed immensely over recent years. Twenty years ago we only knew one of the genes (known as SOD1) behind the rare inherited form of MND. Today, we now know 12 of them. With research into MND growing more and more every year we are hopeful that this research will lead to the likelihood of new drugs and treatments.

While we agree with calls for more drugs to be available to more people and more quickly, achieving this in practice is not easy – if it was, it would have been done by now.

This is why the Association encourages further exploration into the idea of adaptive licensing.

The C9orf72 mystery begins to unravel even more of its secrets

The C9orf72 mystery begins to unravel even more of its secrets

In 2011 an international team of scientists, including three MND Association-funded researchers, identified the elusive C9orf72 gene located on Chromosome 9. Since this ground-breaking discovery, researchers from around the world have been trying to find a way to open-up and reveal more about this MND-causing gene.

Determined to get inside and unravel the secrets behind C9orf72, the Association is funding a number of new and exciting research projects to help solve the mystery. These projects look at, not one, but a number of different aspects to try and understand more about C9orf72.

In order to solve this mystery our C9orf72 researchers are following the clues using zebrafish, mice, flies and DNA samples.

How the C9orf72 MND mystery began

We each contain copies of 23 pairs of chromosomes, including the X and Y sex chromosomes. These chromosomes contain thousands of genes that portray our characteristics such as hair and eye colour. These genes are made up of DNA which can either be ‘coding’ to make a protein, or ‘non-coding’. For details of how genes make a protein see our earlier blog post.

Before C9orf72 was identified researchers had focused on an area on Chromosome 9 that appeared to be connected with both the rare inherited form of MND and the related neurodegenerative disease frontotemporal dementia (FTD).

Using a number of cutting-edge techniques the international team isolated the C9orf72 gene expanded GGGGCC hexanucleotide repeat as being a crucial player in both inherited MND and FTD. Not only did the researchers find a link between MND and FTD, they also found that C9orf72 was found in approximately 40% of cases of inherited MND (where there is a strong family history). This means that we now know 70% of the genes that cause the rare inherited form of MND. For more details on C9orf72 see our earlier blog post.

For more information on inherited MND please see our website.

So, researchers found C9orf72. The next question was ‘What does it do? Is the gene defect repeat itself, or the protein it makes responsible for causing MND? And what goes wrong in MND?’

Following the clues to solve C9orf72

Two recent research clues

Since 2011 researchers have been trying to answer these questions and find out more about C9orf72. This has led to a dramatic increase in research, including two papers published in February and March this year!

Prof Christian Haass (Munich Centre for Neurosciences, Germany), who recently presented at our 23rd International Symposium on ALS/MND in December 2012, published a paper on the 7 February in the journal Science. The second paper lead by Prof Leonard Petrucelli (Mayo Clinic, USA) was published open access in the journal Neuron on the 20 February.

In a big surprise, both researchers found that the presumed ‘non-coding’ C9orf72 GGGGCC repeat expansion actually made a protein. Normally these ‘non-coding’ regions do not make proteins so this was a very big surprise indeed!

The researchers found that these proteins formed large clumps in the brains, and throughout the central nervous system (CNS), of people with C9orf72 MND and/or FTD. Importantly, they did not find these clumps in healthy individuals or those with other neurological disorders.

It is currently unknown as to whether these protein clumps are involved in MND and/or FTD, but they may be a potential biomarker or a therapeutic target in this most common type of MND. The next step is for the researchers to find out whether these proteins actually cause MND and/or FTD.

Finding more evidence to piece together the clues

In addition to these two papers looking into the mystery behind C9orf72, the Association is funding some exciting new research projects, each looking at different things, to further understand more about this gene.

Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Dr Johnathan Cooper-Knock (Sheffield Institute for Translational Neuroscience, UK) is already trying to identify how C9orf72 causes MND by utilising a genetic technique known as gene expression profiling. He is using samples from the Association’s DNA bank which are positive for the C9orf72 genetic mistake. Gene expression profiling is a technique which allows researchers to understand how the activity of genes contributes towards causing MND. (Traditional genetic studies are designed to look at which genes are affected, rather than their activity – ie when and how). Read more about Johnathan’s project here.

Developing new disease models enables us to understand the causes of MND and to test new therapies. One way to understand the function of C9orf72 and how this goes wrong in MND is to create a model. Our current research projects are developing new C9orf72 models in flies, mice and zebrafish.

Dr Frank Hirth (Kings College London, UK) will be producing a fly model, Dr Javier Alegre Abarrategui (University of Oxford) will be making a mouse model and Dr Andrew Grierson (University of Sheffield, UK) will be creating a zebrafish model.

All of these models aim to understand the function of C9orf72 and what goes wrong. The researchers hope to study what happens in MND and how this occurs by looking at behaviour and what happens when C9orf72 is ‘switched’ on and off. For more information about these exciting research projects please see our website.

Solving the mystery

All of our C9orf72 Association-funded research projects are using different approaches to look at C9orf72 in different ways as we are still unsure whether the protein or the repeat is the problem. From mice to flies all of these research projects together are helping to solve the mystery of C9orf72 and MND.

With the proteins formed by C9orf72 likely to be a potential biomarker or therapeutic target the two recent papers are adding to the growing number of clues, pointing researchers in the right direction to unravelling and solving the secrets of C9orf72.

References:

Mori, K. et al. The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS. Science. 339(6125): 1335-1338. 2013 DOI: 10.1126/science.1232927

Ash, P. E. A. et al. Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS. Neuron. 77(4): 639-646. 2013 DOI: 10.1016/j.neuron.2013.02.004

Antisense seems to make sense

Results from a phase I clinical trial of a drug known as ISIS 333611 have been published open-access online in the scientific journal Lancet Neurology on 29 March 2013.

This is the first time researchers have tested the effects of delivering an antisense oligonucleotide directly into the human cerebral spinal fluid (the fluid between the spinal cord) showing that it is both safe and well tolerated in people with the SOD1 form of inherited MND. For information on inherited MND please see our website.

This work suggests that this ‘antisense’ approach may be a good strategy for other neurological disorders.

What is antisense?
Antisense is a type of therapy that causes the ISIS 333611 to directly interfere with the faulty instructions for making a SOD1 protein, thus stopping the production of the disease-causing substance. This is called ‘gene silencing’ as that part of the gene is not ‘heard’ when the final protein is made.

ISIS 333611 works by targeting mRNA, the ‘messenger’ that carries the genetic instructions from the SOD1 gene to the protein-making machinery (for more about mRNA and how proteins are made see our earlier blog post). Instructions in the mRNA for making the SOD1 protein (sometimes called a ‘sense’ sequence) are faulty in people with SOD1 inherited MND, which leads to harmful SOD1 proteins being made.

So if the levels of harmful SOD1 can be reduced, might this be protective? That’s the thinking behind the treatment. By binding to the SOD1 mRNA, ISIS 333611 prevents the production of a harmful SOD1 protein. Indeed, studies in SOD1 positive animal models indicated that reducing the level of SOD1 by antisense therapy increased lifespan. However, targeting the SOD1 gene in this way is a very ‘personalised’ treatment strategy – if it does work it will only work for people who have the SOD1 from of MND.

Results from the trial
Based on the encouraging animal studies, the researchers and ISIS Pharmaceuticals conducted a phase I trial of the antisense oligonucleotide ISIS 333611.

Twenty-one people with SOD1 MND were involved in the study and results from the trial have shown that there were no toxic effects due to increased dosing of the drug and that the drug was safe and well tolerated.

In animal models antisense therapy is found to spread well throughout the central nervous system (brain and spine). However, unlike animal models, the researchers showed that concentrations of ISIS 333611 were lower in the upper end of the spinal cord and brain compared to the injection site. Due to this the delivery site of the drug will probably need to be revisited in future trials.

Dr Pietro Fratta

As this was only a short-term ‘Phase I’ trial it was not designed to test whether this antisense therapy had an effect on MND. This would only be seen with long term treatment and future trials. However, the results are encouraging as they show that this type of therapy is both safe and well tolerated in people with SOD1 MND.

Results make sense

Dr Pietro Fratta (University College London), who is a recipient of a Medical Research Council/MND Association’s Lady Edith Wolfson Clinical Research Fellowship, has written an accompanying commentary on the paper. He said that this study “paves the way for applying antisense oligonucleotides to other forms of genetically determined MND” such as the C9orf72 form of the disease.

However, he stressed that “many hurdles still need to be overcome to bring this treatment to the clinic”.Dr Fratta also cautioned that the longer-term implications of lowering SOD1 protein levels had to be examined. The antisense approach not only targets the harmful mutated SOD1 protein, but will also lower levels of ‘healthy’ normally functioning SOD1, which plays an important role in protecting neurons from damage. So, the antisense treatment approach may be a ‘double-edged sword’ that will require very careful handling.

Reference
Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurology 2013 DOI: 10.1016/s1474-4422(13)70061-9 Read the full article here.

Fratta P. Antisense makes sense for amyotrophic lateral sclerosis C9orf72 Lancet Neurology 2013 DOI: 10.1016/s1474-4422(13)70059-0

Major new research finding raises some old questions

Hot on the heels of ‘Brain Awareness Week’, comes ‘National Science Week’, with the University of Sheffield enthusiastically organising a numerous activities in their week-long Festival of Science and Engineering, including today’s Open Day at the Sheffield Institute of Translational Neuroscience (SITraN). This event was to include talks by Dr Chris McDermott and Prof Pam Shaw on MND and the role that SITraN plays in the search for effective treatments for neurodegenerative disease.

Unfortunately…… last night’s snow has put the kibosh on that, so instead of heading up the M1 to Sheffield, I decided to use some of the saved time to catch up on some reading – in particular a recent paper that came out in the journal Nature, from an international consortium, led by the scientists from the Austrian Academy of Sciences in Vienna.

The best seven pages in ten years

A senior MND researcher emailed me to say it’s one of the best papers he’s read in the past 10 years and I can understand where he’s coming from. Not only does the research identify a previously unknown cellular process that causes selective motor neuron degeneration, but it also appears to tie together several of the pieces of the pathological jigsaw: disruption of RNA metabolism, oxidative stress and programmed cell death pathways.

As impressive is the sheer amount of work that has gone into this seven-page paper. OK, there are also several extra pages of online supplementary material (one of the great benefits of online publication) but I reckon there is the equivalent of at least three PhD theses and several years of work in there!  

In a nutshell, the researchers created a mouse that has a defect in an enzyme called CLP1 and these mice develop progressive motor neuron degeneration. I’m not going to go into the detail, but rather focus on one interesting item that was buried in the text.

Genetic environment matters for CLP1

When researchers initially tried to create the mice they found that the mice all died well before birth. So they tried using a different strain of mice, but got the same result.

A third strain produced live mice, with normal numbers of motor neurons at birth. However from about the age of four months, these mice then developed a progressive muscle weakness and loss of motor neurons over the course of several months.

The paper focuses in on what’s going on in these mice, but it also raised additional questions for me, such as:

“Why did these mice survive into adulthood, when two other mouse strains didn’t – and is there something different in the genetic make-up of these mice that has basically protected them into adulthood rather than killing them as embryos?”

MND Association funded research on genetic environment

Other groups have noticed that when SOD1 mice are bred on different background strains, it can have a profound effect on disease progression and survival. This brings us nicely back to SITraN, as Prof Shaw and her colleagues are looking at precisely this issue, in an MND Association-funded collaboration with Prof Caterina Bendotti in Milan.

They are looking at the gene expression profiles (basically which genes are switched on and off) in the motor neurons of two strains of SOD1 mice, one of which develops the disease and later age and also lives much longer.  By working out patterns that are linked to specific biological processes, they are starting to pinpoint pathways which are driving the disease and also which ones might be slowing the disease. Some of their findings were presented at the most recent International Symposium (Abstract C61).

If there are protective genes at work in the mice, might the same be happening in humans?

The search for ‘good’ genes hots up

I’m often asked about Steven Hawking – how come he’s lived so long?  For years, one of my pet theories has been that there is something in his genetic make-up that didn’t stop the disease from occurring, but is ‘pushing back’. That’s becoming an increasingly popular and productive area of investigation – as genetic researchers extend their focus from finding ‘bad’ genes that cause or predispose people to develop MND, to potentially ‘good’ genes that might slow down the disease. A couple of candidates have been identified, most notably the EphA4 gene.

The search for these disease-modifying genes needs joined up collaboration between researchers around to world and it’s heartening to see how everyone in the field is starting to get together to pool their samples and data, which will allow the genetic profiles of those with exceptionally slowly progressing MND to be analysed in much larger numbers than ever before. If good genes can be identified and their roles understood, it will open up exciting new treatment opportunities.

A Time for New Researchers to Blossom – PhD studentship Applications

It is that time of year again when we open our Online Summary Application Form for our next round of PhD studentship applications, for projects starting in October 2014. The deadline for summary applications is Friday 3 May 2013.

Last Time
Our last round saw an all time record number of studentship applications. We received 18 summary applications and went on to fund five of these attracting new researchers and institutes.

Promising Young Researcher
Our PhD studentship grants allow us to attract and fund promising young scientists starting their careers in MND research and to help us continue to develop the UK basic research capacity. As with all our research projects, we aim to fund the best of the best. Our rigorous application process allows us to ensure we only fund studentships of the highest quality and of direct relevance to MND. To find out more on our application process please see our grant application process.

We are currently funding 15 studentships; five of these are due to start in October 2013.

We hope this year’s PhD studentship round is as exciting as last year!

More Information
For further information on our studentship grants, please see our research we fund and for more details on how to apply for a PhD studentship. Please see our how to apply for funding.

Degenerating Brains

“One in six of over-80 year olds will get a neurodegenerative disease. We’ve got to find ways to slow, stop or reverse these conditions” was the distinctly political message at the opening of this public symposia on “Degenerating Brains: new research into Alzheimer’s, Parkinson’s and Motor Neurone Disease”, run jointly by the Wellcome Trust and the Medical Research Council. The evening began with the world premiere of a short film explaining the importance of continuing to pursue research into these conditions (coming soon to an internet near you.. !).

The lectures started by Prof John Hardy’s excellent overview of genetics, illustrated by advances in Alzheimer’s Disease. “It’s the golden age for being a geneticist” he commented. I particularly enjoyed his explanation of the much quoted research paper by Manolio et al 2009 (Its Figure 1 in this OPEN ACCESS (yeah!) paper –if you really want to look at it!). “There are now recipes for finding causes of diseases that fall anywhere on this graph” Prof Hardy explained. Whether they are rare genetic mistakes that have a big impact (make a big contribution) on whether someone develops a condition) or more common genetic mistakes that have a smaller overall contribution. His closing comment “Geneticists are finding the jigsaw pieces to give to the cell biologist and neuropathologists to put together”, was a theme that the next speaker, Prof Chris Shaw, continued.

Prof Shaw, MND Association grantee, eminent scientist and clinician based at King’s College London, began his talk by laying down a challenge to the younger generation of scientists in the audience “I’m banking on you to find the answers to my degenerating brain”. He went on to explain how the discovery of genetic mistakes in SOD1, TDP-43 and FUS has led us to a greater understanding of the biological pathways involved in motor neurone degeneration in MND. Prof Shaw’s research has led him to develop close relationships with families affected by the rare, inherited form of MND and he ended his talk with a thank you to them for their help.

The concluding presentation was given by Prof David Rubenstein from Cambridge University, describing how advances in understanding Huntingdon’s disease research will act as a model for driving advances in other neurodegenerative diseases.
The consortia of funded researchers have got together to create a blog site for posts about Alzheimer’s Disease, Motor Neurone Disease or Parkinson’s Disease, why not add this link to your favourites too (and if you’re a twitter fan, you can follow them @dneurons ) http://degeneratingneurons.wordpress.com/.

Access to understanding MND research

Brain Awareness Week  got off to a good start for me. Last night I attended the awards ceremony for a joint competition run by the British Library and Europe PubMed Central (Europe PMC). I met many people dedicated to explaining their research to non-experts and making the research available as widely as possible. Motor neurone disease research was included in the mix.

The aim of the ‘Access to Understanding’ competition was to promote two important aspects of all research – the ability to get details of new research findings – the reports written up as research ‘papers’ – to as many people as possible, as soon as possible. The second was the ability to be able to explain the same research to non-experts. Both of these are important to researchers and the possible beneficiaries of the research too.

About a year ago, MND Association grantee Professor Siddharthan Chandran and colleagues published an important MND research paper. It described a new way of studying why motor neurones die in MND. Using skin cells from patients with a specific form of the rare, inherited MND, the scientists were able to create living human motor neurones using ‘iPS’ technology. These motor neurones showed signs of developing MND – so they can be used to understand more about the disease. More information about this study and other stem cell research underway is available on our website.

Importantly the research paper describing these results is available for free on the research database Europe PMC. The paper was published ‘open access’ – an increasingly used method of making the results available / accessible to as great a number of people as possible.

The Association requires all new grantees to publish their research papers using the open access model. It’s part of our commitment to ensure that MND research knowledge is used and shared as widely as possible – moving us faster towards a world free of MND. More information on our open access policy  is available on our website.

The Europe PMC database contains the full details of over 2 million research papers. We and the other 18 funders of the database selected a total of nine research papers to be used in the competition. In January, scientists at an early stage in their careers were invited to choose one of these nine papers to write a non-expert summary.

Prof Chandran’s research paper was one of those selected. More than 400 entries were received, from researchers around the world. Over 30 were submitted summarizing the MND research paper. Colleagues at the British Library, Europe PMC and each of the research funders were involved in judging the entries. A final judging panel of six experts chose the winner and two runners up from a shortlist of 14 entries.

Nina Rzechorzek’s article ‘A window into brain disease is only skin deep’ was shortlisted from the MND articles submitted. You can read a copy of Nina’s article on our website (see ‘Summary of 2012 iPS paper’ link).

Nina Rzechorzek’s article ‘A window into brain disease is only skin deep” was shortlisted

“It is so easy to get drawn into the details and forget why the question was asked in the first place” she explained, when I asked her why she entered the competition. “A really great theory should make sense to everyone. I enjoy the challenge of getting people excited about neuroscience”.

“I think it is essential for any scientist to be able to take a step back from their work, think about why it is important and communicate their objectives and findings to a wider audience. This is not about ‘dumbing-down’ complex ideas, but presenting them in a readily-digestible format to get the fundamentals of the scientific content across. The same rules apply in the clinic when explaining a disease process or treatment plan. Understanding empowers the listener/reader and builds trust.”

Many congratulations to Nina and the other shortlisted authors. In particular, congratulations to the overall winner, Emma Pewsey for her winning entry ‘Hip hip hooray’ describing a new study that might predict why hip fractures occur.

At the awards ceremony last night, we heard the top tips from the judges on what they were looking for in the competition entries and some though provoking ideas for promoting a greater scientific understanding for everyone.

And I do mean everyone! Last night it was acknowledged that researchers themselves don’t have to move too far from their specialist areas before it becomes difficult to understand. One of the judges commented: “it was only when I read the competition entries that I understood the science”.

Brain Awareness week

Every March, Brain Awareness Week (11 – 17 March 2013) unites people of all ages worldwide to raise awareness of brain research. There are 45 free events across the UK, including seminars and school visits.

On the evening of the 11 March Belinda attended the free award ceremony for the winner of the Europe PubMed Central-led science writing competition ‘Access to understanding’, which included a large number of entries on an MND paper.

On the 13 March University College London (UCL) will be running a free public symposia on ‘Degenerating Brains’. As well as talks on Alzheimer’s and Parkinson’s disease, Prof Chris Shaw (King’s College London) will be speaking about MND. Due to the popularity of this event it is now fully booked.

Our Brain Research

Dr Martin Turner

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

Continuing and expanding  BioMOx Dr Martin Turner has also been awarded his second MRC/MND Association Lady Edith Wolfson Clinical Research Fellowship to carry on his BioMOx project which is to begin in August 2013.

Dr Turner will be broadening the BioMOx project to include people identified as being at risk of developing MND from families with a history of the disease but who are not yet showing symptoms.

Dr Ramesh Tennore

Dr Tennore Ramesh’s interneuron findings A recent study by Association funded researcher Dr Tennore Ramesh from the Sheffield Institute for Translational Neuroscience (SITraN) has shown that even before the symptoms of MND occur, at the earliest stages of the disease, ‘connector neurones’ known as interneurons are already becoming damaged in the zebrafish.

Prof Mara Cercignani’s MRI scans project Starting in October 2013 Prof Mara Cercignan’s Association funded PhD studentship will use brain magnetic resonance imaging (MRI) scans that have already been obtained from many studies at King’s College London over the past 16 years.

This project will apply new ideas in medical computing to old data in order to identify how MRI changes in the brains of people with MND evolve. This will then enable the development of a new method to ‘stage’ MND progression so that brain abnormalities can be detected earlier.

Tissue Donation and MND

Tissue donation is a generous gift that can make a vital contribution towards MND research. Researchers investigating MND are particularly interested in the whole of the brain and spinal cord tissue, otherwise known as the central nervous system (CNS).

A brain and spinal cord tissue donation is made from either a healthy individual or somebody with MND after their death. To find out more information about tissue donation please see our information sheet on our website.

Raise Awareness of MND

I Am Breathing

Our 2013 Awareness Month campaign is focussed around a film called I Am Breathing. The hard-hitting documentary tells the story of Neil Platt, who was diagnosed with MND just after his son, Oscar, was born.

Neil wanted to leave a legacy for Oscar and also raise awareness of MND. We hope that thousands of people will see the film on or after a special Global Screening Day, Friday 21 June, Global MND Awareness Day.The Association has joined forces with the film makers, the Scottish Documentary Institute, and with Neil’s family to make sure this powerful story is shared as widely as possible when the film is released during the Awareness Month in June 2013.

You can help fulfil Neil’s goal of raising awareness by hosting your own screening of I Am Breathing on 21 June 2013 – MND Global Awareness Day.

MND stem cell study identifies TDP-43 astrocytes as not toxic to motor neurones

Funded by the MND Association, international researchers have used stem cell technology to learn more about the relationship between motor neurones and their support cells.

These findings highlight the potential of stem cell technology as a tool to create new human ‘in a dish’ cellular models of disease to learn more about the causes of MND.

The research group included MND Association funded researchers Prof Siddharthan Chandran and Sir Prof Ian Wilmut from University of Edinburgh, Prof Chris Shaw from King’s College London and Prof Tom Maniatis from Columbia University in America.

This important finding was published in the scientific journal PNAS on 11 February 2013. This new finding follows on from previous work published by this research group in 2012 where they demonstrated the proof of principle of creating human motor neurones with MND in a dish.

Why we need an astrocyte model of MND

Astrocytes, so called because of their star-like appearance, normally act as neurone support cells to nourish and protect motor neurones. They act with motor neurones to ensure that they can continue to function.

From previous studies, we know that when these cells begin to dysfunction, they can become toxic to motor neurones to contribute to MND. Finding out why astrocytes can cause motor neurones to degenerate is an issue of ongoing debate – we recently gave an update on this from the International Symposium.

Being able to grow human astrocytes in a laboratory dish is of importance to be able to learn more about the relationship between astrocytes and motor neurones in MND.

Creating human astrocytes in a dish

Using cutting-edge stem cell technology, the research group reprogrammed skin cells into astrocytes in a laboratory dish. The skin cells were donated by people with MND who have a family history of the disease caused by known mistakes in a gene called TDP-43.

Led by Prof Chandran and colleagues, the research group aimed to identify whether these cells would develop the ‘hallmarks’ of MND in a laboratory dish.

By studying the characteristics of these human astrocytes with faults in the TDP-43 gene, the research group identified that they shared the same qualities as cells affected by MND. The astrocytes had increased levels of TDP-43 found in areas where it isn’t usually found – outside of the control centre of the cell. They also found that the astrocytes didn’t survive as long as astrocytes created from skin cells of people that didn’t have MND.

This means that the human astrocytes created by Prof Chandran and colleagues using stem cell technology develop MND-like characteristics. This new model can be used to study how motor neurones develop the disease in a system that is directly relevant to people living with MND.

Answering whether faulty astrocytes affect healthy motor neurones

The next question that this research group wanted to answer was whether these faulty astrocytes had an effect on healthy motor neurones.

By growing faulty TDP-43 astrocytes with healthy motor neurones, the research group identified that the survival of motor neurones was not adversely affected.

This was surprising as other research groups have shown that when astrocytes have faults in the SOD1 gene (which cause one in five cases of MND with a family history) that motor neurones are compromised, even if the motor neurones were originally healthy.

TDP-43 is found within tangled lumps in over 90% of cases of MND (irrespective of whether it was caused by an inherited genetic mistake). However, when MND is caused by SOD1, TDP-43 is not found in these tangled lumps. This important difference could be leading to the key difference in whether astrocytes become toxic to contribute to causing MND.

These findings will of course need to be verified by an independent research group to determine that they are valid, but the results suggests that SOD1 and TDP-43 could be causing havoc in motor neurones in slightly different ways, both avenues leading to MND.

Our Director of Research Development, Dr Brian Dickie comments: “From a therapeutic perspective this is important because it means that specific treatments targeted at astrocytes may only be relevant and effective, in specific subsets of patients who will have to be carefully selected for drug trials.”

References:

Our news release on this finding.

March 2012 finding: Association-funded stem cell study achieves milestone

Serio A et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. PNAS 2013

Zebrafish show that ‘connector neurons’ are the key in early stages of MND

A recent study by Motor Neurone Disease Association-funded researcher Dr Tennore Ramesh from the Sheffield Institute for Translational Neuroscience (SITraN) has shown that even before the symptoms of MND occur, at the earliest stages of the disease, ‘connector neurones’ known as interneurons are already becoming damaged in the zebrafish.

Dr Tennore Ramesh

Zebrafish are ideal models for helping scientists understand what happens in MND. Unlike mice and fly models, zebrafish have transparent embryos which enable scientists to get a unique view of the developing neurones under a microscope! Scientists can also look at disease progression in adult zebrafish by looking at muscle strength and measuring their progress swimming against a current.

Not only are zebrafish useful for helping scientists understand what happens in MND, they are also an ideal drug screening model. Zebrafish and humans are more similar than you may think (see Kelly’s post) and potential new MND drugs can be screened quickly. Looking at how MND progresses in the zebrafish, before symptoms appear, can help us gain a better understanding of what causes the disease.

Motorways, dual carriage ways and slip roads

No, I’m not writing about travel alerts or the latest roads disruptions due to flooding or snow. In fact, these road systems happen to be a perfect example of what interneurons are, how they relate to motor neurones and what goes wrong in MND.

Our body consists of two types of motor neurones, which are known as upper and lower motor neurones. The upper motor neurones are found in the motor region of our brain and connect to the spinal cord. The lower motor neurones are found between the upper motor neurones in the spinal cord and connect to the muscles (e.g. in the arms and legs). Interneurons are the vital connections between the upper and lower motor neurones.

Interneurons are the ‘slip roads’ between upper and lower motor neurons

When a signal is sent from our brain to bend an arm it starts by travelling down an upper motor neurone. The signal then travels to a lower motor neurone via an interneuron. When the signal from the lower motor neurone reaches the muscle in our arm it causes the muscle to contract and bend.

In MND these upper and lower motor neurones become damaged and they are unable to transport the nerve signal from the brain to the muscle in our arm. This means we are unable to contract and bend, even though the brain is telling it to.

­­­In our road system scenario the upper motor neurones are the motorways (e.g. the M1), and the lower motor neurones are the dual carriageways that link the motorways to nearby towns (e.g. the A38). In order for an upper motor neurone to send a signal (e.g. a car) to a lower motor neurone it needs to go via an interneuron, which in our road system scenario is a ‘slip road’ – making these interneurons vital connections between motor neurones.

This study has given us a better understanding of what happens in MND at the early stages of the disease (before symptoms occur). The researchers found that interneurons became damaged before the motor neurones themselves. Therefore this shows that interneurons are important in the early stages of the disease and scientists can begin to look at ways of preventing interneuron damage to see whether this has an effect on MND.

Adding more evidence to the puzzle

This study showed that, in zebrafish, interneurons are involved in the early stages of MND, which adds further evidence to previous work by another MND Association-funded researcher. Dr. Martin Turner (Oxford) also found damaged interneurons at the early stages of the disease before symptoms of MND occur in humans, with other studies showing interneuron damage in SOD1 mice models.

The next step would be to look at ways of preventing these interneurons from becoming damaged, to see whether this has any effect on the progression of MND.

This research is the first article we have paid to be made available Open Access, so that it is freely accessible to all. The article was published online in the prestigious journal ANNALS of Neurology on the 31 December 2012.

Paper reference:

McGown, A. et al. Early Interneuron Dysfunction in ALS: Insights from a mutant sod1 Zebrafish Model. ANNALS of Neurology 2012 DOI: 10.1002/ana.23780 http://onlinelibrary.wiley.com/doi/10.1002/ana.23780/abstract