Developing a drug screen using nerve cells from a mouse model of MND

In a previous research project funded by the MND Association, Prof Kevin Talbot and colleagues from the University of Oxford developed a new TDP-43 mouse model of MND. Compared to other mouse models of MND, this one accurately reflects the symptoms of the disease and levels of the TDP-43 protein as seen in humans.

TDP43 location in the cell
Location of TDP-43 protein (shown in red) in healthy nerve cells, and how it moves into different parts of the cell in MND

This model of MND also shows how the TDP-43 protein becomes displaced from the nucleus (command centre of the cell) out into the cell cytoplasm, which makes up the cell body. Once TDP-43 has moved to the cytoplasm it is very difficult to shift, as it forms protein aggregates or clumps. It is thought that these clumps contribute to motor neurone cell death.

Prof Talbot’s latest project, together with researcher Dr David Gordon, is using cultured nerve cells from this new mouse model to screen a large library of drugs (our project reference: 831-791).

In the next two years, they will create an automated computerised imaging system that can detect the TDP-43 protein within the nerve cells (and see if it has moved out of the nucleus). With this imaging software the researchers aim to screen thousands of drug compounds in a short space of time, including some which have been approved for other illnesses. A ‘good’ drug will make TDP-43 stay in the correct location within the nerve cell’s nucleus.Read More »

Protecting motor neurones against oxidative stress in MND

During the early stages of MND it is proposed that motor neurones are more susceptible to an imbalance of oxygen within the cells, known as oxidative stress. Prof Dame Kay Davies, at the University of Oxford, has previously shown that increasing the levels of the gene Oxr1 can protect motor neurones from death caused by oxidative stress and delay MND in mice. You can read about this work here.Read More »

On the fourth day of Christmas MND research gave to me: a new stem cell research project

“On the fourth day of Christmas MND research gives to you… on the FOURTH month of 2014, we announced that we’ll fund an exciting new stem cell project”

Prof Linda Greensmith, University College London
Prof Linda Greensmith, University College London

During our April Biomedical Research Advisory Panel Meeting we agreed to fund seven new MND research projects. These projects included Prof Linda Greensmith’s research on Restoring muscle function with transplanted stem-cell derived motor neurones.

Based at University College London, this study will use stem cell technology to restore muscle function in a mouse model of MND. The researchers will transplant stem-cell derived motor neurones and then guide them to where they’re needed using light.

Prof Greensmith and her team aim to restore function to the muscles that are responsible for breathing and develop an optical stimulator, which can then be implanted into the body to stimulate the transplanted cells for long periods of time. If successful, this technique could form the basis of future treatments that could potentially restore muscle function in MND.

Click here to read more about the research that lead to us funding this project

What’s all the ‘FUS’ about?

Prof Vladimir Buchman (Cardiff University)’s research was selected as one of the best research studies, as decided by the journal editors, published in the Journal of Biological Chemistry in 2013. He is building on this research in his Association-funded project, which began on 1 April 2014.

The background to FUS:

In 2009 an international team of scientists, including researchers funded by the Association, identified the FUS gene as a cause of approximately 4% of inherited MND cases (5-10% of total MND cases).

The FUS protein formed by this gene is usually found in the nucleus or ‘control centre of the cell’. A change in the structure and/ or function of the FUS protein leads to motor neurone damage and the development of MND. This change causes the FUS protein to ‘wander’ outside of the cell nucleus and form protein ‘clumps’ within the cell.

These protein clumps, as well as being found in 4% of inherited MND cases, are found in many cases of MND and the related disease, frontotemporal dementia. At present it is still not clear how this happens and how these clumps of FUS protein cause MND.

Read More »

Switching the light on for MND

MND Association-funded researcher, Prof Linda Greensmith, based at University College London, together with her collaborator Dr Ivo Lieberam from Kings College London, have introduced stem cell-derived motor neurones into mice. Published in the prestigious journal Science on 4 April 2014, her research has also demonstrated that muscle function can be controlled by light.

Modelling MND

MND Researchers use a range of models to further our understanding of MND. These can be animal models, such as mice and zebrafish, or cellular models, such as induced pluripotent stem (iPS) cell-derived motor neurones (as described by Association-funded researcher, Dr Ruxandra Muthiac, during the Spring Conference in Newport on Sunday 6 April).

These models enable us to find out more about the causes of MND by studying how changes in the genes (our genetic makeup) give rise to MND. Not only this, models of MND are the essential ‘first step’ in screening potential new MND drugs before they go on to human trials.

Prof Greensmith and her team of researchers used an early stage mouse model of MND. By using this model she was able to investigate if embryonic stem cell-derived motor neurones could be successfully transplanted into mice and whether muscle function could be controlled by light.

Read More »

Same disease.. two very different mice!

The exact course, duration and rate of progression of MND often varies greatly from person to person; even when there is a known family history of the disease caused by a specific MND-causing gene (eg SOD1).

This same variability also occurs in mice. Researchers, funded by the MND Association, took two mice with the same SOD1 gene mutation from two different families (strains). By using these two mice the researchers identified a number of key changes in motor neurones that differ between fast and slow progressing forms of the disease.

Two mice… One gene

The SOD1 mouse
The SOD1 mouse model has been one of the most important MND research tools for scientists

Developing new disease models enables us to both understand the causes of MND and test potential new therapies.

Mice are commonly used in MND research and for the past 10 years or more, the SOD1 mouse model has been one of the most important research tools for scientists working in the field, particularly with testing potential new therapies.

Research published in September 2013 was carried out in a joint collaboration between Dr Caterina Bendotti (Mario Negri Institute for Pharmacological Research, Milan Italy) and Prof Pam Shaw (University of Sheffield, UK).

Read More »

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.

Changing fashions of MND models

Models of MND are important both to understand the causes of MND and to quickly, efficiently and accurately screen and develop new treatments for it.

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.