Paving the way towards better clinical trials

“The annals of ALS clinical trials is strewn with failed studies. Only two out of more than 70 clinical trials have been positive, and even these showed only very modest benefit.  Is this dismal record strictly due to the extraordinary complexity of neurodegenerative disease in general, and ALS in particular?  Or is it due to methodological flaws that could be repaired?” 

Robert G Miller, Professor of Neurology, Stanford University

Although there is not much we can do about disease complexity, improving the way treatments are trialed is something that can be achieved. Imagine a world without clinical trials, where independent companies or individuals would be allowed to sell their self-made ‘drugs’ without any evidence that they were ever used on anyone with the disease, let alone that they would improve one’s condition. No one would know what the drug is (which could simply be a water solution), how it works and whether as soon as the drug is taken, we would be poisoned.

Thankfully, this is not the case and clinical trials, although not perfect, are considered the gold standard for approving any treatment.  However, there are still some improvements that can be done to make trials easier to access and provide more accurate estimates of drugs’ effectiveness much faster.

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Drug repurposing – harnessing the positive side effects of ‘old school’ drugs

Is it possible that a drug that treats congestive heart failure could improve respiration in people with MND? Or that a drug used to treat cancer could reduce motor neuron inflammation and possibly slow progression of the disease? In this blog we take a look at drug repurposing – using a drug developed to treat a particular disease to treat another that is unrelated – what it is, and what it might mean for people living with MND.Read More »

Professional football and MND – looking at the evidence

Last year professional football players, Len Johnrose and Stephen Darby, announced they’d been diagnosed with motor neurone disease (MND). This follows previous announcements from other prominent footballers in this country and across the world in recent years.

Is it the case that professional football players are more prone to developing MND than the general population? Or is this just the impression created by the high-profile nature of these professionals and the corresponding media coverage these cases bring? What does the science suggest?

Here we look at some of the studies that investigate the incidence (rate of newly diagnosed cases) of MND in professional football players and take a closer look at the suggested causes.Read More »

GLT8D1: new gene identifies novel disease mechanism

MND Association-supported clinical fellow Dr Johnathan Cooper-Knock, and a PhD student Tobias Moll, report mutations in a new MND gene which has uncovered a previously unknown disease mechanism. The new MND causing gene holds instructions for a class of proteins, called glycosyltransferase (GLT8D1), which has not previously been associated with neurodegeneration.

During the experiments, published in the journal Cell Reports, the research team read the genetic code from two related patients with an unknown familial (inherited) form of MND and found a change in the gene that makes an enzyme called GLT8D1. They went on to examine a larger sample of 103 people with inherited MND and found that five of these also had this gene abnormality, indicating that this change causes MND. Because the enzyme and its mechanism have never previously been associated with MND, this study has uncovered a new genetic and biological cause of the disease.Read More »

Kennedy’s Disease: focus on muscle damage reveals key biomarker

Findings from the largest biomarker study of people with Kennedy’s Disease, published in the journal Neurology, found a predictive biomarker to help in differential diagnosis and tracking clinical progression. Led by Dr Pietro Fratta from University College London, the research team highlighted the importance of markers of muscle mass rather than neuronal damage in Kennedy’s Disease, differentiating it from the slightly more common motor neurone disease (MND).

Kennedy’s Disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a rare genetic condition that leads to progressive weakening and wasting of muscles, particularly affecting the limbs and bulbar region. Caused by a mistake on the AR (androgen receptor) gene (positioned on the X chromosome), this condition mainly affects males, with a 50% chance of receiving the affected gene from their mothers (women can only be carriers of the genetic mistake without developing the disease).

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Energy and metabolism in MND cells answer the burning question

Despite the winter chill, there is a warm fuzzy feeling today with the news of a paper published in the journal ‘Brain’ by an MND Association funded Research Fellow, Dr Scott Allen. Based at the Sheffield Institute for Translational Neuroscience (SITraN), Dr Allen was awarded a Senior Non-Clinical Research Fellowship by the Association in 2016, and we are immensely proud to have been able to play a supporting role in his work.

Dr. Allen giving a platform presentation at the International Symposium on MND/ ALS in December.
Dr Allen giving a talk at the International Symposium on MND/ ALS in December 2018.

In his paper, Dr Allen and his colleagues took a novel approach to understanding how MND affects the pathways that are important for making energy in cells of the central nervous system (CNS), that are crucial to keep motor neurons functioning and alive. Specifically, his work has pinpointed a specific mechanism that is changed in MND. The team also demonstrated that there is the potential to tackle this issue by circumventing the problem in order to maintain a critical energy balance in the CNS, and therefore potentially identifying a significant new target in the development of future treatment.

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Cannabis-based products for medicinal use

In November 2018 the Home Office released a draft Guideline scope for Cannabis-based products for medicinal use in which they announced that specialist doctors (like consultant neurologists) on the Special Register of the General Medical Council will be able to prescribe cannabis-based medicinal products to some patients. Before this, the only cannabis-based medicines licensed for use in the UK were nabiximols (Sativex), used as a treatment for spasticity (where muscles are continuously contracted, causing stiffness or tightness of the muscles, interfering with normal movement and speech), in multiple sclerosis (MS).Read More »

Disease mechanisms: Highlights from Glasgow

This blog is part of the ‘Highlights from Glasgow’ collection of articles, where you can read about the content of some of the talks and posters presented at the 29th International Symposium on ALS/MND.

Several sessions at the Symposium focused on how impairments in key neuronal structures in MND contribute to the development and progression of the disease, and how these could be targeted with therapeutics.

Prof Spires-Jones (C16) opened session 4A with a discussion of the role of synapses in neurodegeneration. Synapse dysfunction and loss is seen in many neurological diseases, including MND, Alzheimer’s disease and Dementia with Lewy bodies. The commonality of synapse loss across these diseases makes it a key therapeutic target, and in addition, most neurological drugs work at the level of synapses, making them a very ‘druggable’ target. Prof Spires-Jones summarised data from her team and others that showed that in MND, synapse degeneration in the frontal cortex is associated with cognitive decline, and damaging TDP-43 protein is found in synapses. Targeting these pathways could be beneficial to prevent or treat MND.

We also heard an interesting talk from Prof Schiavo in session 5A (C29) on the use of axonal transport as a therapeutic target. Deficits in axonal transport are found in many neurological diseases, including MND.  These deficits appear before/at disease onset and are likely to be important in the development of MND. Schiavo talked us through data that showed that the p38 MAPK signalling cascade, which is important for axonal transport, is increased in the SOD1 mouse model of MND, and that long-term treatment with a p38 MAPK inhibitor partially restores physiological function in MND neurones in vitro and in vivo. Another example showed that inhibition of the insulin-like growth factor-1 receptor (IGF1R) (which is overexpressed in MND patients) restores axonal retrograde transport in a SOD1 mouse in vivo, providing further evidence of the possible beneficial effects of targeting key pathways linked to axonal transport. The take-home message was that axonal impairments are reversible and can be modulated by small molecule inhibitors.


Find out more about the topics discussed in Glasgow on our Periodic table of Symposium at www.mndassociation.org/symplive.

Cognition and FTD: Highlights from Glasgow

Written by Rachel Boothman and Kaye Stevens

This blog is part of the ‘Highlights from Glasgow’ collection of articles, where you can read about the content of some of the talks and posters presented at the 29th International Symposium on ALS/MND.

Exploration into cognition and frontotemporal dementia with MND/ALS continues to attract attention. At the Symposium in Glasgow 2018, we heard of several studies adding to the growing knowledge bank in this field.

A history of other mental health conditions or psychiatric disorders within the family, or for the individual, indicates a correlation with MND/FTD. There seems to be a link between this increased history and a risk of apathy. Early screening is recommended where these histories exist. This can help prepare families and enable early discussions with the person diagnosed with MND, so they can make decisions that may be important to them in the future (C41) C McHutchison.Read More »

What’s the story with CuATSM

There has recently been a flood of news stories on the outcomes of the Australian Phase 1 clinical trial investigating Copper ATSM (CuATSM) which is a small man-made compound that can selectively deliver copper to cells. The results were first presented at our International Symposium in Glasgow back in December.

MND is a terrible disease and anyone affected by it is looking for good news. We really hope that CuATSM will provide a new treatment for MND that is going to have a positive effect on people’s disease progression.

However, CuATSM is not yet at a stage where a clinician can prescribe it as a treatment. Drug development is a long journey, where any drug has to pass important rigorous checks before approval as a medicine. This trial is an important ‘first’ in the drug development process.

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