A PERK for neurodegenerative disease?

Our bodies need to be able to make new proteins, to maintain long term memory. So if the ability to make new proteins is switched off, does this cause Alzheimer’s Disease? New research findings published yesterday by scientists based in Leicester take us closer to answering this question. Journalist are describing this as a step forward for all neurodegenerative disease, so I wanted to explain what the researchers found, and what it might mean for MND.

What’s the story?

The activated form of a chemical called ‘eIF2’, is found in higher levels than normal in the brains of Alzheimer’s Disease patients. (In it’s turn, eIF2 is activated by an enzyme called PERK – hence the name of the blog post.. !).

Last month (September 2013) researchers found that genetically blocking the activation eIF2 prevented memory problems in a mouse model of Alzheimer’s Disease. The research published yesterday showed that in a mouse model of prion disease, chemically blocking eIF2 (as opposed to genetically blocking it) helped prevent the development of prion disease (Variant CJD or ‘mad cow disease’ is an example of a prion disease).

The chemical block was given to mice orally (one of way of doing this is to give it to them in their food). It got to the brain OK and effectively blocked eIF2, but the chemical did have serious side effects. So it’s a possible turning point for drug treatment for Alzheimer’s Disease and prion disease, but not the answer.

Read More »

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”

The 11th Annual ENCALS meeting highlights how TDP-43 spreads in MND

The European Network for a cure of ALS (ENCALS) held its 11th Annual meeting in Sheffield from 31 May to the 2 June. The weekend was full of glorious British sunshine and more than 200 international scientists and clinicians were also able to enjoy a range of incredibly interesting talks about the latest developments in MND research.

A particular talk caught my attention on the first day by Dr Johannes Brettschneider from the University of Ulm in Germany. Dr Brettschneider explained how his research had shown the stages and spread of the protein TDP-43 in ALS (the commonest form of MND).

Dr Brian Dickie, Director of Research Development, said: “The key to defeating MND lies in fostering strong collaborations between neurologists, healthcare professionals, research scientists, early career investigators and students in the field of MND and the 11th Annual ENCALS meeting in Sheffield provided that opportunity. The MND Association was proud to support this event.”

‘Special’ staining

At the end of an afternoon of talks on the MND- causing genes C9orf72, FUS and SOD1, Dr Brettschneider engrossed over 200 delegates with his talk on the TDP-43 protein and how it spreads in ALS.

Although TDP-43 genetic mistakes are a rare cause of MND, scientists are especially interested in the TDP-43 protein because in the vast majority of cases of MND (irrespective of whether it was caused by an inherited genetic mistake), TDP-43 protein forms pathological clumps inside motor neurons.

The study (which is a collaboration between Dr. John Trojanowski and Dr. Virginia Lee from the Penn University Center of Neurodegenerative Disease Research in Philadelphia, America and the group of Dr. Heiko Braak in Ulm) used a technique known as ‘immunohistochemistry’.  This technique involves taking tissue samples of the brain and spinal cord from people who have died from ALS. The researchers would then make extremely thin slices of the tissue, which could then be stained using a ‘special stain’ and viewed under a microscope.

The stain used by Dr Brettschneider only ‘stained’ the TDP-43 protein in the samples, meaning that he could see the amount of TDP-43 in different areas of the brain and spinal cord.

Using the clinical information and TDP-43 staining this would allow Dr Brettschneider to stage the disease.

Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.
Image kindly provided by Dr Robin Highley, SITraN: (top left) a motor neurone with a skein-like neuronal cytoplasmic inclusion, next to a normal motor neurone (bottom left) on TDP-43 immunohistochemistry.

Axonal ‘telephone wires’ do more than just talking

Dr Brettschneider showed that TDP-43 increased in different areas of the brain and spinal cord during different stages of the disease. Amazingly, he also showed how ALS (characterized by clumps of TDP-43) spreads from one are of the body to another.

A motor neurone consists of three parts; the cell body, axon and nerve ending. The cell body contains the nucleus, or the control centre of the cell. When a message travels from the brain the cell body sends the message down the axon. Like telephone wires, the axon carries the message to the muscle, where the nerve endings cause the muscle to move.

However, in ALS it seems that these ‘telephone wires’ do more than just carry a message. The protein TDP-43 forms ‘clumps’ in the motor neurones and it seems that these clumps use the axon to travel from one motor neurone to the next (possibly explaining why someone get’s weakness in their arm and then their hand).

Another key finding was that TDP-43 clumps develop in the front part of the brain (prefrontal cortex), which is responsible for personality and may explain the development of cognitive symptoms.

Dr Brettschneider explained the importance of this research While spreading of disease-related proteins has been described for other neurodegenerative diseases like Alzheimer’s disease or Parkinson’s disease, this had not been previously shown in ALS. Now, we can show evidence that supports a spreading of the major disease protein TDP-43 in ALS across specific regions of the brain and spinal cord with ongoing disease.

 If these findings can be confirmed (for example in cell culture or mouse model studies) then this could lead to the design of new treatments specifically aiming to impair the spread of TDP-43 protein clumps.

Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS
Dr Johannes Brettschneider from the University of Ulm in Germany at ENCALS

Furthermore, we believe that our findings offer a better understanding of disease progression in ALS.  Our data implies that TDP-43 spreads throughout the prefrontal cortex with ongoing disease, thereby lending support to the idea that all ALS patients could eventually develop “frontal type” cognitive deficits.”

The future

Dr Brettschneider commented why this research is important to people living with MND explaining that “If these stages can be reproduced in patients with ALS they could offer a new way to assess disease progression and response to new treatments. We hope that our study provides the essential groundwork for strategies designed to prevent pTDP-43 spread.”

This research is only the beginning and more work is needed, Dr Brettschneider also explained what he hoped to do next with these exciting results. “There were restrictions in time and availability of the tissue samples during this study, so we were unable to determine how and where exactly ALS begins in the very early stage of the disease. Therefore, an important next step in our work would be to analyze very early cases with ALS to look at TDP -43 spread as this offers the most promising window for therapeutic intervention.”

Reference

Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 May 20. doi: 10.1002/ana.23937. [Epub ahead of print]

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 Research in 2012

Word cloud from our 2012 blog posts. Created from wordle.net
Word cloud from our 2012 blog posts. Created from wordle.ne

At this time of year, it’s always good to look back on the previous year to see just how far we’ve really come. We’re pleased to say that 2012 was full of progress being made in the world of MND research and we hope that the speed and number of exciting findings being announced continues at this pace in 2013.

In 2012, 1,466 scientific papers were published in MND, which is 200 more than the previous year, demonstrating the energy and speed at which progress is being made.

Twitter: If you follow us on Twitter, then we’d like to take this opportunity to thank you for your re-tweets and mentions throughout 2012 to help raise awareness of MND and to keep your friends and family up-to-date with our exciting news. We managed to double our followers in 2012 because of your continued support!

News stories:

We wrote over 30 blog articles in 2012 to take you behind the scenes of MND research. These were viewed over 36,000 times with visitors coming from 126 countries. Here’s an over of a few of the findings we wrote about in 2012:

Clinical trials

At the start of the year, we heard some exciting news that a drug called Cogane produced some encouraging results in an MND Association funded study. A few weeks ago we heard an update that the drug company who owns Cogane called Phytopharm are moving toward a clinical trial and are currently securing funding and support for this. This could  take a number of months before final plans are made but it’s positive to see that MND Association funding has led to this exciting development!

It was also positive to hear some encouraging NP001 clinical trial results for MND, which is leading toward a larger Phase III study to test the effectiveness of this drug in MND in America this year.

Angiogenin findings advance our understanding of MND

In June, we heard that Irish Angiogenin research lead to promising results. One finding was related to a new biological finding of the vital role that angiogenin plays and the second expands on this work and led to the testing of angiogenin in mice that model MND. Later on in the year, we also heard how University of Bath research showed how angiogenin affects motor neurone survival.

New genes

We also heard about some exciting findings in understanding how genes can influence survival and cause MND for some people. In July, Profilin1 was identified as a cause of MND. In our blog, we explained that Profilin 1 has a role in holding the shape of the cell through the cells scaffolding – called the cytoskeleton. We then heard about another gene called EPHA4 which influences survival in MND.

EPHA4 also plays a role in the cytoskeleton which means that researchers can explore this pathway in more detail as it, in conjunction with the Profilin 1 finding, suggests that this guidance/growth system of motor neurones may play an important role in the development of MND.

Advancing our understanding of C9ORF72

Since the discovery that a repeat expansion in the C9ORF72 can cause MND in 2011, researchers have been working to understand more about it. We announced that we would be funding a new Fellowship which aims to explore how C9ORF72 causes MND using our DNA bank samples. Very late in 2012, we also heard that MND Association funded researchers had identified the structure of C9ORF72 repeat, which looks (with some artistic license granted) surprisingly like a Battenberg cake! It will be interesting to see this field of research continue to yield exciting developments over 2013 and beyond.

TDP-43 research in yeast

TDP-43 was identified as a cause of inherited MND for approximately 4-5% of people with a positive family history of the disease in 2008. Since then, researchers have been working to identify how this gene can cause MND and how this system could be targetted to develop a new treatment for MND. In November, we wrote about a study which marked the first steps in the identification of a treatment that can target TDP-43, which is found to clump together in over 90% of cases of MND. Using a novel yeast model, the research group identified that they could reduce the toxic effect of TDP-43 as a potential therapy for MND.

As this is the beginning of the story of TDP-43 specific treatments for MND, it will inevitably be a long journey to answer these questions and to bring treatments to the doctor’s prescription pad. However, it is positive that this research is moving forward and that we are moving in the right direction.

Symposium 2012

One of the highlights from our year is always our International Symposium on ALS/MND. It’s an accumulation of over a year’s worth of work for our Research Development Team and is a fantastic platform that really demonstrates how far research has come in a year.

For our 2012 International Symposium on ALS/MND, we received 419 high quality overviews of research (called abstracts) from across the globe, totaling 172,581 words!

Over 900 researchers, clinicians and healthcare professionals from 30 countries attended our sympsoium in Chicago USA in 2012 to hear 86 platform presentations and to see over 300 poster presentations.

To keep you up to date with news from the symposium, delegates used the Twitter hashtag #alssymp. In total, 950 tweets were sent using this hashtag!

We also blogged live from the symposium to bring you news as it broke, we summarised these findings in our Symposium highlights 2012. There’s still time to share your thoughts about our symposium blogging to assist us with plans for 2013! To take part, please visit www.surveymonkey.com/s/alssymp.  We will be closing this survey on 31 January.

Thank you!

For following news from the ever changing world of MND research on the MND Association’ research blog, we would like to thank you! We hope you enjoy reading our blog posts in 2013 and help us to raise awareness of MND and the pace of research by sharing our news stories with your friends and family!