What goes wrong with electrical signalling in MND?

Last year, we introduced a PhD Studentship that we are funding at the University of St Andrews. Under the supervision of Dr Gareth Miles and Prof Siddharthan Chandran, the student working on this project, Amit Chouhan, is investigating why electrical signalling goes wrong in MND.

As the project enters its second year, Amit and the team have made some important discoveries… Continue reading

Using stem cell technology to understand more about how MND and FTD develop

The MND Association are funding Prof Kevin Talbot, Dr Ruxandra Dafinca (née Mutihac) and colleagues at the University of Oxford, who are investigating the link between the C9orf72 and TDP-43 genes in MND. We wrote about this research earlier in the year. As we’ve recently received their first year progress report we wanted to give you an update on what they’ve achieved. Continue reading

Stem cell trials in the news

The recent announcement about the use of stem cells to treat a form of multiple sclerosis (MS), together with early results from the BrainStorm stem cell amyotrophic lateral sclerosis (ALS) clinical trial in Israel have raised the profile of stem cells as a possible treatment for motor neurone disease.

Stem cells are unspecialised cells in the body which do not yet perform a particular function. They can renew themselves and have the ability to give rise to different types of cell, including nerve cells (motor neurones and the surrounding support cells).

Both the ALS/MND study (ALS is a type of motor neurone disease) and the MS study used stem cells found in bone marrow taken from the patient, and then given back to the same patient later on in the process. The MND study gave a new use to the bone marrow stem cells, whereas in the MS study ‘corrupt/damaged’ stem cells were replaced with a new healthier set.

Below we look at both trials in more detail and describe what they mean for people living with MND. Continue reading

Buckets more research – some of our plans for the Ice Bucket Challenge money

Today’s announcement of the difference the ALS / MND ice bucket challenge has made included a number of areas of research investment. You’ll be hearing much more about these as our plans develop, but here are three examples to give you a flavour of things to come.

ibc oxford

Oxford researchers get an icing!

Continue reading

Human Motor Neurones

Dr Jakub Scaber is a Medical Research Council (MRC)/  MND Association Lady Edith Wolfson Clinical Research Fellow who works in Professor Kevin Talbot’s Laboratory at the Oxford University. Like Prof Chandran’s research, Dr Scaber’s fellowship is also investigating stem-cell derived motor neurones, here he blogs about his research.

jakub mn image

This is an image of motor neurons.

But not just any motor neurons – these are motor neurons that have been derived from skin cells of one of our patients who was a carrier of the most common mutation in the rare inherited form of MND (5-10% of total MND cases) – a mutation in the gene C9orf72. Continue reading

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.

Continue reading

Stem cells and growth factors: from bench to bedside

After a brilliant first day at ENCALS, which included a talk by Dr Johannes Brettschneider, the second day began with a talk by Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute) arriving directly from attending at the Anne Rowling Regenerative Neurology Symposium.

Prof Svendsen gave a riveting talk to over 200 delegates, explaining his research on treating ALS (the commonest form of MND) with stem cells and growth factors, and the journey taken from bench to bedside.

The talk began with Prof Svendsen explaining his earlier research into Spinal Muscular Atrophy (SMA) – a genetic disease which causes severe paralysis in children. He explained how he and his collaborators took skin cells that had been banked for over 10 years from a patient with SMA and ‘reprogrammed’ them back into stem cells which were then pushed forward again into motor neurones. Stem cells are ‘immature’ cells, which have not yet ‘matured’ into a specific cell type (eg nerve cell or heart cell). Prof Svendsen’s research was similar to that by Prof Chandran (who did a post-doc with Prof Svendsen) who took skin cells from an MND patient.

Mo Le Cule on our stand at ENCALS

Mo Le Cule on our stand at ENCALS

A little bit of everything is good for you

Like red wine and chocolate (which are both allegedly good for us in moderation) Prof Svendsen highlighted that “a little bit of everything is good for you ” particulary with regards to radiation.

Radiation is a word that people associate with cancer and being dangerous but Prof Svendsen explained that low doses of radiation actually increases DNA repair.  Work by Dr. Seigo Hatada at the Cedars-Sinai Regenerative Medicine Institute has shown that when induced pluripotent stem (IPS) cells are given a low dose of radiation in the lab this enhances the ability to put new genes into the stem cells (homologous recombination) an important technique needed to either label the cells or correct bad mutations.   This is a very important new finding that may help the stem cell field in the future.

Ageing astrocytes

Astrocytes are support cells that are known to play an important role in keeping motor neurones healthy. SOD1 astrocytes (positive for the SOD1 MND-causing gene) were previously found to be toxic to motor neurones but TDP-43 astrocytes were found not to be toxic. Prof Svendsen showed that aged wild type (normal ‘healthy’) astrocytes were also toxic to motor neurones, suggesting that ageing of these cells may have an important role in MND.

Not only were the aged adult wild type cells toxic, they were almost as toxic  as a SOD1 astrocyte (upto 40% more than foetal wild type astrocytes)!

Astrocytes are the key

Replacing damaged motor neurones with stem cells, or healthy motor neurones, is just not possible today”. This is because motor neurones have incredibly long connections and replacing them in the body is a hard thing for researchers to do.

Prof Svendsen explained that replacing astrocytes offered a much better alternative. This is because astrocytes are easy to transplant and are sick and aged in MND. His approach, as described previously at the Anne Rowling Regenerative Neurology symposium, involves a combination of gene therapy and stem cells. Prof Svendsen converted human stem cells into astrocytes and then genetically modified them to produce large quantities of a nerve protecting factor called glial-derived neurotrophic factor (GDNF).

Genetic modification of these astrocytes was carried out by infecting them with a harmless virus. This virus then inserts a gene into the astrocyte, which enables it to produce and secrete GDNF. These modified astrocytes are then inserted into one side of the spinal cord of a SOD1 rat (expressing signs of MND). Prof Svendsen successfully showed that these astrocytes secreted GDNF and protected the motor neurones in the rat at the side of the transplant.

Prof Svendsen explained that the modified astrocytes do not seem to cross to the other side of the spinal cord and are only a ‘partial protection mode’ which means they don’t affect paralysis. They do, however, protect the healthy motor neurones. It is important to note that these experiments used the SOD1 rat model. Only 20% of inherited MND cases have the SOD1 MND-causing gene so this model is not a complete representation of other inherited and sporadic MND cases.   It is now important to try these exciting new stem cell and growth factor treatments directly in patients – they are the only real representation of the disease.

A phase I clinical trial after twelve years of research

Prof Svendsen concluded his talk by mentioning that with funding from the California Institute for Regenerative Medicine (CIRM) he is seeking U.S Food and Drug Administration (FDA) approval for a phase I/IIa clinical trial, which aims to transplant these genetically modified astrocytes into the lumbar (lower) spinal cord of ALS patients.

This trial plans to begin in 2015 by transplanting the GDNF secreting astrocytes into one side of the spinal cord to see the effects on the patient’s legs. Because, the astrocytes can’t cross the spinal cord, this will mean that the researchers will be able to compare both legs to look for differences in disease progression. The trial is double-blinded (with only the surgeon knowing which side the astrocytes are transplanted) and is across three centers in America. Prof Svendsen mentioned that he is on track for the first patient in 2015 providing the safety studies in animals work out as planned.

Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute)

Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute)

Prof Svendsen stressed that this has been a long road and shows just how long it takes to go from making observations in the lab to a clinical trial (he started this work back in 2003).

What next?

Prof Svendsen’s research has shown a great deal of work; including how he converted stem cells into astrocytes, showed that aged wild type and SOD1 astrocytes are toxic to motor neurones, found that GDNF prevented motor neurone death and the start of his clinical trial in 2015.

Prof Sevndsen commented on what the future might be. “If this therapy is found to be effective in ALS patients during this phase I/IIa trial we plan a much bigger trial!! We would aim to move from protecting the legs to protecting respiration – as we have shown the cells can work there too.”

Finally, Prof Svendsen stated what this research means to people living with MND with two simple words. “New hope”

Anne Rowling Regenerative Neurology Symposium

The sun was (uncharacteristically!) shining on Edinburgh last week for a symposium to celebrate the launch of the new Anne Rowling Regenerative Neurology Clinic. The clinic, which opened to patients earlier this year, was founded following a donation by the author JK Rowling, in memory of her mother, who died from complications related to multiple sclerosis (MS).  Run by Professors Siddarthan Chandran and Charles ffench-Constant, the clinic aims to translate laboratory research into clinical trials for neurodegenerative diseases such as MS and MND.

Anne rowling logo

The programme for the two-day meeting was packed with ‘big hitters’ from the world of neurology. In keeping with the regenerative neurology theme, the opening session was chaired by Sir John Gurdon, recent co-winner of the Nobel Prize for physiology and Medicine, whose pioneering work on cell cloning set the foundations for the more recent development of induced pluripotential stem cells, which are currently revolutionising medical research.

Different diseases, common challenges

The first day was given over to research areas such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease, as well as spinal injury and pain. What was also apparent is that different fields of neurology are wrestling with similar challenges: to diagnose disease earlier, ideally even before symptoms occur; to find biomarkers that tell us about the changes occurring in the Central Nervous System(CNS) at different stages of disease; to really understand the order in which these different aspects of pathology (the study and diagnosis of disease) occur and, given the theme of the conference, to sift the cellular changes caused by disease from the body’s attempts at cellular repair. All of these feed into the greatest challenge – how to take this accumulated knowledge from bench to bedside.

We can learn a lot from diseases that are further ahead in this process, such as the excellent overview by Prof Alastair Compston (Cambridge) on MS. It’s becoming clear that MS has distinct disease stages, starting off as an inflammatory disease, but progressing to a more ‘traditional’ neurodegenerative disease in more advanced stages. Whist there has been some considerable success in treating the former, the approaches to the latter have, as with MND, met with very limited success.

The use of imaging techniques to work out what is happening within the brain has been a vital factor in drug development for MS. As Prof David Miller (University College London) pointed out, magnetic resonance imaging (MRI) can pick up positive changes in small MS drug trials that are not large enough to show changes in disability. This sort of biomarker-based evidence gives drug companies the confidence to invest in the larger, much more expensive trials needed to show a clinical effect.

A presentation on the imaging of pain by Prof Irene Tracey (Oxford) provided a fascinating insight into the power of the placebo effect. She explained how neuroimaging has helped researchers to identify the brain regions associated with placebo effects and also gave examples of studies where the placebo effect has performed as well as (and even outperformed) commonly used painkillers! The power of placebo can be very strong indeed and it is important to always ensure that trials are rigorously performed to account for this.

Parkinson’s disease has always been viewed as a promising candidate for cell transplantation therapy, but clinical studies over the past 30 years have produced mixed results. Profs Roger Barker (Cambridge) and Anders Bjorklund (Lund University) discussed the various reasons for this ‘heterogeneity of response’ and how these are being addressed in the plans for a pan-European study.

In terms of cell transplantation, the approaches that will need to be taken for MND are very different from those for Parkinson’s disease. In Parkinson’s disease the strategy is to try and replace some of the key neurons that have died, but due to the immense length of human motor neurons, such a strategy of rewiring the nervous system is highly unlikely to work for MND. However, there are other approaches that can be taken, as Prof Clive Svendsen (Cedars-Sinai Medical Center) explained.

His approach involves a combination of gene therapy and stem cell therapy. By converting human stem cells into astrocytes, which are cells known to play an important role in keeping neurons healthy. By genetically modifying these cells to produce large quantities of a nerve protecting factor called glial-derived neurotrophic factor, and injecting them into the spinal cord of SOD1 rats, he has shown that the surviving motor neurons can be protected. He is in the process of gearing up for a phase 1 therapeutic trial in up to 18 carefully selected MND patients.neuron

Disease in the dish

Prof Svendsen also briefly spoke about the promising research arising from the use of induced pluripotential stem cells (iPSCs) to study MND – a topic taken up in much more detail by Prof Jeff Rothstein (Johns Hopkins University) who highlighted recent advances in understanding the C9orf72 form of the disease.

It may be possible to create specially tailored gene therapy approaches for some forms of familial (inherited) MND, as is currently being attempted in SOD1 MND. Prof Rothstein’s initial work using iPSC-derived motor neurons suggests that this approach is also worth considering for the more common C9orf72 from as well.

Prof Steve Finkbeiner (University of California) who is collaborating in the Association-funded international stem cell initiative elaborated on the use of iPSCs as a tool for drug discovery, demonstrating how fully-automated robot-based systems can be used to follow the fate of thousands of individual human motor neurons in the dish over a prolonged time period. The great thing about robots is that they don’t need sleep, so can analyse the cells at all times of day and night. They do, however, have Twitter accounts, so they can report in to the centre staff when they have completed their experiments!

One of the exiting prospects of using these automated systems is the potential to screen thousands of compounds. If human motor neurons can be protected in the dish, there are no guarantees, but it at least shortens the odds that the human motor neurons can be protected in the human as well. There are still many improvements that can be made to the process, but screening work is underway, with a particular focus on drugs that stimulate cellular process called autophagy (a process in which a cell breaks down damaged components), which is believed to be protective across a number of neurodegenerative diseases.

There were many take home messages from this meeting, but what was abundantly clear from all the work presented was the enthusiasm of each speaker for their field of research and an optimism that we are on the cusp of major advances in understanding neurological conditions. Sharing of new knowledge across the various diseases and disciplines can only bring those advances closer.

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.

Prof Siddharthan Chandran and Sir Prof Ian Wilmut at University of Edinburgh looking at a stem cell image

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

The clinical trials session

A very much ‘must report on’ session of the 23rd International Symposium on ALS/MND was the clinical trials and trial design session. There are many reasons that make this an interesting session – perhaps the most eagerly anticipated were the presentations on the NP001 study and the results of the stem cell safety trial:

NP001 update

We reported on the blog on 1 November the results of the NP001 study, and these findings were confirmed today by Dr Bob Miller from Forbes Norris Centre in California USA. The trial showed that intra-venous administration of NP001 was found to be generally safe and well tolerated, with a modest clinical benefit seen in the high dose (2mg/kg) group.

As previously reported in their press release, ‘post-hoc analysis’ (meaning literally after the event), showed that some patients in the higher dose group did not have any change of a scale that measures the functional capabilities of people with MND called the ALS-functional rating scale (ALSFRS) over the course of the study. Historical controls were used in the post-hoc analysis – the first time that the US Food and Drugs Administration (FDA) had allowed them to do this.

The room was packed and there were five people queuing to ask questions about this talk. Questions were asked about the use of historical controls; the possibility that patients would identify that they were in the treatment group due to the presence of a ‘burning feeling’ at the injection site; and about other forms or ways of taking NP001. On the last of these points, a question about the chemical structures of NP001 and WF10 went unanswered.

But Dr Miller was categoric about different ways of taking NP001. “Taking NP001 in any other route [than intra-venously] is unsafe and unproductive”.

Results of stem cell safety trial

The first regulatory body (FDA) approved phase I safety trial of a stem cell treatment for MND, conducted in America, is now complete. Dr Johnathan Glass from Emory ALS Center, Georgia USA presented the results of this study.

In the last 5-10 years there has been a huge amount of interest from MND researchers, clinicians and patients alike about the possibility and potential for using stem cells to treat MND. More information about what stem cells are and how they might help is available on the MND Association’s website.

As for any other drug or potentially beneficial intervention, the first part of the assessment should always be to obtain a robust and objective measure on whether such a treatment is safe, and this is what the NeuralStem study was designed to find out.

A team of highly trained specialists, in close consultation with the FDA, designed a study to look at the safety of giving an injection of stem cells directly into the spinal cord of people with MND. Eighteen surgeries were performed on fifteen patients – three of these patients volunteered to have two surgeries (two injections).

The first three people with MND recruited into the study received a single injection of stem cells on one side of the bottom (lumbar) of the spinal cord. The next three received injections on both sides of the lumbar spinal cord. These first six patients were at an advanced stage of MND, where they were unable to walk.

The next six patients, who were able to walk, received injections at one or both sides of the lumbar spinal cord. The last three patients received a single injection higher up the spinal cord (cervical) and finally, the three patients able to walk who received a single lumbar injection underwent a second surgery to receive a single cervical injection.

The results from the first six patients has already been published in a scientific paper:

Stem Cells 2012 30(6) 1144 – 51

Dr Glass concluded that the procedure is well tolerated and safe and that there is no indication that the surgery accelerates the progression of the disease. The next phase of the study, giving injections into the cervical spinal cord at increasing doses (numbers of cells) is funded and is awaiting FDA approval.

Our International Symposium website news stories:

International Symposium closes in Chicago

International Symposium focuses on clinical trials

International Symposium focuses on carer and family support

International Symposium begins in Chicago

Researchers unite at our International Symposium on MND

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