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.Read More »
This year the Symposium session on clinical trials looked at three drugs and one therapy. Dr Brian Dickie has posted a separate blog on one of these drug treatments – Edaravone.
A summary of the results from the drugs and treatments discussed is below. More information on each of them in detail is later on in this blog.
Ibudilast: This drug was safe and well tolerated in those who were not using non-invasive ventilation. However, these are results from an early stage trial so more research is needed to establish possible long-term benefit.
Methylcobalamin (Vitamin B12 injections): If this treatment is given early (within 12 months of diagnosis) then it showed an effect at increasing survival in a small sub-group of those taking part in the trial. This effect was not seen when the treatment was given further on from diagnosis.
Stem cell therapy: This small, early Phase 1/2 trial was testing the safety of bone-marrow derived stem cell injections into the spinal cord. The researchers found this treatment had no major side effects. Further studies are needed to evaluate the effectiveness and safety of this treatment over the long-term.
Bar a few bacteria usually found hitching a ride on our dental plaque and digestive system, every living cell in the human body needs oxygen. Some cells need more oxygen that others, dependent on much energy they need to produce to function. Neurones are particularly active cells (the brain uses a fifth of all the oxygen consumed by the human body) and motor neurons are amongst the most energy hungry of all.
Unfortunately, the process of producing cellular energy isn’t 100% efficient: a small but constant amount of waste products called free radicals (yep, those things that the beauty product industry bangs on about) can build up in the cells. If not kept in check, they can start to wreak havoc within the cell.
Our cells have quite effective ways of dealing with free radicals, but these ‘cellular defences’ become less and less efficient with age. As we age, our energy production processes lose efficiency, causing a ‘double-whammy’ of not only more free radicals being produced, but also less effective ways of dealing with them. When neurones are damaged, as happens with neurodegenerative diseases, then everything gets exacerbated even further, leading to a vicious cycle of events.Read More »
Unfortunately, although the drug was found to be safe, the results concluded that Tirasemtiv did not meet its primary objective, showing no difference in disease progression, as measured by the ALS Functional Rating Scale (ALSFRS) compared to placebo matched controls. Cytokinetics Inc have stated that further study of Tirasemtiv is needed.
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.
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.
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