Results from the UK clinical trial of diaphragm pacing in MND/ALS (known as DiPALS) were published online today in the journal Lancet Neurology.
DiPALS was the first randomised clinical trial of diaphragm pacing in MND and aimed to find out whether or not diaphragm pacing was beneficial when added to the current standard treatment of non-invasive ventilation (NIV), compared to NIV treatment alone.
The trial results unfortunately show that diaphragm pacing was not beneficial when used in addition to NIV, and was in fact harmful, with people using diaphragm pacing living on average 11 months shorter than those on NIV alone.
A number of articles were published in various news sources on 11 July 2014, highlighting how scientists in Sheffield are working towards testing a promising treatment for a rare inherited form of MND caused by the SOD1 gene. Here we write about the research and what it means for people living with MND.
The Sheffield Institute for Translational Neuroscience (SITraN) specialises in research into MND and other neurodegenerative diseases. Recently the institute received an anonymous donation of £2.2 million to help translate their research from the lab to the clinic. This is a huge amount of money into MND research and this donation will enable the researchers to further our understanding of the disease.
We know that approximately 10% of cases of MND are inherited. This means that they are characterised by a strong family history and the disease is caused directly by a mistake in a specific gene. Of these 10% of cases, 2% are caused by the SOD1 gene (meaning that for every 100 cases of MND, 10 cases are inherited and of these, only 2 are directly caused by the faulty SOD1 gene).
Prof Mimoun Azzouz’s research at SITraN was reported in a number of news outlets, highlighting how his research is paving the way to a treatment for a rare form of MND. His research is at a relatively early stage, where he has only just begun investigating the use of a technique known as ‘gene therapy’ in mice affected by the SOD1 inherited form of MND. If the research goes to plan, he will be able to submit a proposal for regulatory approval by August 2015.Read More »
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.
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.
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.
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).
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”