Our mission is to empower and enable patient & public involvement in motor neuron disorders research

News Archive: 2020

November 2020

New members welcome!

Can you help researchers understand Patients’ & carers’ priorities?

The aims of the Research Advisory Group are to:

  • Enable the perspectives of patients and carers to be included in research proposals
  • Provide knowledge from each member’s experiences of MND
  • Identify and prioritise research topics from the patients’ perspective
  • Improve recruitment to research studies
  • Help identify improved treatments from research results
  • Give patients and carers a more authoritative voice
  • Help build public credibility and trust in clinical research
  • Improve the input from patients and carers to research projects
  • Identify any barriers to patient’s effective involvement in research
  • Comment on “Patient Information and Research Results Sheets”
  • Help write lay summaries for research proposals
  • Raise public awareness of MND research

If becoming a member interests you and you would like to find out more about the group (you would be welcome to attend a meeting and visit SITraN) please email Annette Taylor at smndrag@sheffield.ac.uk

The Person Specification, Terms of Reference and Membership Form are available to download here

November MND Research Article summary – Ben Hall, PhD student, University of Sheffield

Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral SclerosisTrial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

Paganoni, S., Macklin, E.A., Hendrix, S., Berry, J.D., Elliott, M.A., Maiser, S., Karam, C., Caress, J.B., Owegi, M.A., Quick, A. and Wymer, J., 2020. Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis. New England Journal of Medicine, 383(10), pp.919-930.

There are currently only two therapies available for the treatment of ALS, Riluzole and Edaravone. Part of the reason for the lack of efficacious treatments is due to the complex nature of the disease, with many factors hypothesised to impact its progression. Included amongst these factors are dysfunctional mitochondria, the part of the cell responsible for energy generation, and a dysfunctional endoplasmic reticulum, the part of the cell responsible for the synthesis of proteins. Researchers now believe that a novel treatment that targets these areas could provide a viable therapy for ALS.
The study, published in the New England Journal of Medicine, investigates the effect on ALS patients of oral consumption of Sodium Phenylbutyrate-Taurursodiol (SP-T), a treatment which combines sodium phenylbutyrate (a.k.a. Buphenyl, Ammonaps or triButyrate) and taurursodiol (a.k.a. Tauroursodeoxycholic acid), and has shown promise in experimental models of ALS. This combination of treatments has two effects;
1. Sodium phenylbutyrate increases levels of heat shock proteins, which are proteins produced in response to stressful conditions that alleviate the effect of a dysfunctional endoplasmic reticulum, stabilising newly synthesised protein by ensuring they are folded correctly, a key stage of protein production in the cell.
2. When mitochondria are distressed they release signals that trigger cell death, known as apoptosis, taurusodiol prevents these signal from being released, preventing the initiation of apoptosis.
The trial was a randomised, double-blind trial, meaning that of the 177 participants (all having developed ALS within the preceding 18-months), 137 were randomly assigned a prescription of SB-T and the remaining 48 given a placebo, with neither the patient or healthcare provider knowing which medication was being taken. The primary outcome being investigated was changes in ALSFRS-R score over the course of the 24-week trial, a measure of the functional ability of the patient, which usually declines over time. Other secondary outcomes such as muscle strength were also observed.
Results showed that whilst there were no significant changes in secondary outcomes in patients taking SP-T, there was a significantly slower decline in ALSFRS-R score. A longer-term trial, screening more patients and measuring survival as a primary outcome will be required before more concrete conclusions can be drawn on this novel treatment for ALS, but this data still represents a huge finding for ALS patients and may mean SP-T will be commercially available as therapy in the coming years.

November MND Research Article summary – Sarah Roscoe, PhD student, University of Sheffield

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus is Associated with ALS and Links Weight Loss to the Disease Genetics, (Iacoangeli et al., October 2020, Cell Reports, Vol 33, Issue 4., DOI:10.1016/j.celrep.2020.108323)

Accounting for 65-85 % of MND cases, amyotrophic lateral sclerosis (ALS) is an incurable, progressive neurodegenerative disorder. Although frequently overlooked, people living with ALS (plwALS) often experience problems with their nutrition, with approximately 16 – 53 % of plwMND becoming malnourished and experiencing significant weight loss during the course of the disease. Weight loss is known to be a factor responsible for speeding up the progression of MND, and shortening life expectancy. It is therefore important to monitor and understand changes in the nutritional status of plwALS. Currently, this is done by measuring people’s weight and body composition; which can be broken down into the proportion of body fat and ‘nonfat’ mass (i.e., everything else in the body, including bones, organs and muscles).

Genes are instruction manuals for the cell, made from sections of DNA; genes tell the cell what to do. Variations from the correct sequence of DNA within a gene are called mutations. The entire set of an organism’s instructions is known as a genome. These instructions have been identified and named in genetic databases.

ACSL5 is a gene known to play a key role in the conversion of nutrients from food and fluid intake into fatty acids (the building blocks of fat in the body). Mutations in the ACSL5 gene have previously been linked to rapid weight loss. The authors of this report conducted a large-scale analysis of three independent ALS genetic databases, comparing the entire genomes of 86,196 individuals (22,877 plwALS and 63,319 healthy controls) across multiple ethnicities (Chinese, European and Australian). They noticed a change in the DNA sequence of ACSL5 in plwALS, but not in the healthy controls.

They then investigated the effect of this change within the ACSL5 gene with body composition, body mass index and weight in 77 plwALS and 77 healthy controls. For 67/77 plwALS, they were able to compare weight and body composition measurements taken during the course of the disease, with the presence of the ACSL5 mutation. They noticed that patients with the ACSL5 mutation had a much lower muscle mass than healthy individuals, which declined more rapidly, over a shorter period of time. This means that the development of ALS is sped up for these individuals, resulting in a shorter life expectancy.

Whilst this report highlights the involvement of ACSL5 in weight loss in ALS patients, these results are unable to distinguish whether ACSL5 causes weight loss as a result of ALS, or whether ALS is a result of weight loss, due to variations within ACSL5. A larger sample size, with measurements collected over a longer period of time are needed to make more certain conclusions between ACSL5 and its involvement in weight loss in ALS.

August 2020

August MND Research Article summary – Jessica Allsop, PhD student, University of Sheffield

Jessica Allsop, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS (Miller et al., July 2020, The New England Journal of Medicine, Vol 383, No. 2., DOI: 10.1056/NEJMoa2003715)

MND is a currently incurable neurodegenerative disorder, that affects motor neuron function. Around 10% of cases are familial, thus having a genetic component, with mutations in the superoxide dismutase (SOD1) gene accounting for 2% of these cases. The mechanism in which this mutation works is thought to be via a toxic gain of function, thus increasing the amount of mutant protein in the body, which can be harmful. There are currently multiple clinical trials that are underway which are aiming to find a potential therapy, including this ascending-dose trial (a trial with multiple groups, each being given a higher dose than the last). In this trial, they designed the antisense oligonucleotide, Tofersen, an artificially engineered piece of RNA (a single stranded piece of DNA used in the making of proteins) to identify mutant SOD1 RNA. This then broke down the mutant SOD1 RNA by activating enzymes (proteins that speed up chemical reactions in the body) to do so. This meant that the mutant SOD1 protein couldn’t be made, thus reducing the levels of mutant SOD1 in the body.

By using individuals affected by MND, with this trial focusing on those affected by mutant SOD1, researchers at multiple universities across the world, in conjunction with the University of Sheffield, aimed to use the antisense oligonucleotide Tofersen to reduce the effects of MND by targeting the mutant form of SOD1, and decreasing the production of this protein. They did this by randomly assigning 50 patients in a 3:1 ratio, with one patient going to the placebo (a deliberately ineffective treatment) group, to each of the following dose groups: Placebo, 20mg, 40mg, 60mg and 100mg. Milligrams (mg) are 1/1000th of a gram, e.g. 20mg is equal to 0.02 grams. Each patient then got 5 injections of their assigned dose into their spinal cord over the course of 12 weeks.

48/50 patients got all 5 doses successfully. There was a reduction in the concentration of the mutant SOD1 protein in the spinal cord in all cases, including the placebo group with a 3% decrease, but the largest decrease was in the 100mg group where there was a 36% decrease in SOD1 concentrations in the cerebrospinal fluid from baseline levels. Cerebrospinal fluid is a clear fluid in the central nervous system that cushions the brain and spinal cord from injury, and also provides nutrients. There was also no difference in the effects of Tofersen with those who were classed as fast-progressing MND and those who weren’t.

This stage of the study could not go beyond this level of analysis. Overall, this therapy provides an interesting target, which does show some benefits. These benefits show a slowing in the decrease of the ALSFRS-R score (ALS Functional Rating Scale Revised), slow vital capacity (volume of air expired in an unforced manoeuvre), and the handheld dynamometry score (measurement of strength in 16 muscle groups), with 100mg Tofersen treatment. However, as they are descriptive tests, it is hard to draw conclusions from this data. Phase 3 of this trial is currently underway monitoring the safety and effectiveness of Tofersen, and the long term effects.

July 2020

July MND Research Article summary – Jessica Allsop, PhD student, University of Sheffield

Jessica Allsop, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model (Keeler et al., December 2019, Molecular Therapy: Methods & Clinical Development, https://doi.org/10.1016/j.omtm.2019.12.007)

    Respiratory insufficiency is normally the cause of death for many diseases, MND/ALS included. Around 10% of MND cases are familial, which means that there is a genetic component. Gene therapy is a method that can be used to correct defective genes and has been used in the treatment of MND. Genes are made up of DNA, a molecule which contains information that alters the characteristics of an individual. Previous research has been conducted using gene therapy to decrease the expression of defective MND-associated genes and increase survival in MND mice. However, these previous gene therapies, did improve survival, but the end result was that the mice died due to respiratory failure.

    By using a mouse model of MND, which was engineered to produce a mutant version of SOD1, a common cause of MND, the researchers at the University of Massachusetts Medical School, Massachusetts, in conjunction with those at Duke University in North Carolina, aimed at targeting the respiratory motor neurons and muscles in order to increase survival. They did this by injecting a virus which was altered to recognise mutant SOD1 and alter the levels of its expression, into mice at 60 days of age. They injected into the tongue and the tissue that covers the lungs, hoping that there would be a decrease in the level of mutant SOD1, thus increasing the respiratory function, and extending lifespan.

    Injecting the mice with this altered virus reduced the mutant SOD1, in respiratory muscles, as well as the spine and other organs such as the liver, heart and hindlimb. The results also showed that injecting mice significantly increased the survival of SOD1 mice, by around 50 days, along with increasing their weight, by around 15%. Neurological function is an indicator of MND, and this therapy has shown that there is a delay in the decline of their neurological function, such as how the mouse reacted when suspended by its tail, or if the mouse could right itself within 30 seconds of being placed on one side. A deterioration in the muscle strength is also common, and this therapy also shows a less rapid decline in this, when compared to untreated mice.

    The study demonstrates a significant increase in survival of MND mice when the respiratory system is targeted. With the death of patients normally being due to respiratory failure, therapy that targets the respiratory system could be essential in aiding survival.

    New members welcome!

    Can you help researchers understand Patients’ & carers’ priorities?

    The aims of the Research Advisory Group are to:

    • Enable the perspectives of patients and carers to be included in research proposals
    • Provide knowledge from each member’s experiences of MND
    • Identify and prioritise research topics from the patients’ perspective
    • Improve recruitment to research studies
    • Help identify improved treatments from research results
    • Give patients and carers a more authoritative voice
    • Help build public credibility and trust in clinical research
    • Improve the input from patients and carers to research projects
    • Identify any barriers to patient’s effective involvement in research
    • Comment on “Patient Information and Research Results Sheets”
    • Help write lay summaries for research proposals
    • Raise public awareness of MND research

    If becoming a member interests you and you would like to find out more about the group (you would be welcome to attend a meeting and visit SITraN) please email Annette Taylor at smndrag@sheffield.ac.uk

    The Person Specification, Terms of Reference and Membership Form are available to download here

    July MND Research Article summary – Ben Hall, PhD student, University of Sheffield

    Ben Hall, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

    CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis (1/3/2020; doi: 10.1093/brain/awaa039)

      Frontotemporal dementia (FTD) is a disease that causes degeneration of the areas of the brain that control cognitive, auditory and visual function. Amyotrophic lateral sclerosis (ALS) and FTD exist on the same spectrum, with many overlapping disease-causing mechanisms. For example, the leading cause of both ALS and FTD is a mutation in the C9orf72 gene. Ordinarily this gene provides a template for production of the C9orf72 protein, but mutation impairs this, triggering development of either disease . Constant work is being carried out to illuminate the causes of ALS/FTD in order to find as yet elusive therapies. Researchers from the University of Sydney now believe they have identified a new genetic mutation that results in the development of these conditions and could help in the search for treatments.
      In 2013 research into an Australian family, genetically predisposed to develop either ALS or FTD and without a mutation in any known ALS genes, showed a mutation in the gene for cylindromatosis lysine 63 deubiquitinase (CYLD) (Dobson-Stone et al., 2013). At the time this mutation was assumed not to be disease-causing; a recent publication in Brain now suggests this may not be the case.
      Dobson-Stone et al. (2020), set out to further investigate the mutant gene reported in 2013. They first analysed brain samples from two deceased member of the family, finding the CYLD mutation caused significant levels of CYLD-immunoreactivity, a measure of the brain’s immune response, suggesting CYLD was in fact harmful. Their next goal was to investigate whether the mutation would have any effect in a cellular model. To do this they expressed the mutated CYLD gene in mouse neuron cells finding that, most notably, the CYLD mutation impaired cellular autophagy (the body’s method for clearing out damaged cells) and altered the location of TDP-43 protein in the cells, two clinical hallmarks of ALS/FTD. Mechanistically, the mutation caused an increase in activity of the CYLD protein, indicating the CYLD mutation is disease-causing due to a gain of function (as opposed to a loss of function).
      CYLD is therefore a cause of, and link between ALS and FTD, albeit a rare one. Though this discovery does not necessarily mean immediate changes for patients it highlights a new disease-causing mechanism that could be applicable in wider ALS/FTD. Further research should now focus on establishing the how common this mutation is (in this study it was only observed in this family and not other, larger databases of patients) and more in-depth investigations in to the mechanisms behind CYLD ALS/FTD.

      References
      Dobson-Stone, C., Luty, A.A., Thompson, E.M., Blumbergs, P., Brooks, W.S., Short, C.L., Field, C.D., Panegyres, P.K., Hecker, J., Solski, J.A. and Blair, I.P., 2013. Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12. 1–q12. 2: genetic, clinical and neuropathological analysis. Acta neuropathologica, 125(4), pp.523-533.
      Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A.M., Chatterton, Z., Carew-Jones, F., Shepherd, C.E., Stefen, H., Paric, E., Fath, T. and Thompson, E.M., 2020. CYLD is a causative gene for frontotemporal dementia–amyotrophic lateral sclerosis. Brain, 143(3), pp.783-799.

      June 2020

      June MND Research Article summary – Jessica Allsop, PhD student, University of Sheffield

      Jessica Allsop, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

      6-Deoxyjacareubin, a natural compound preventing hypoxia-induced cell death, ameliorates neurodegeneration in a mouse model of familial amyotrophic lateral sclerosis (Hoshino et al., March 2020, Neuroscience Research, https://doi.org/10.1016/j.neures.2020.02.011)

      The central nervous system, consisting of the brain and spinal cord, uses a lot of oxygen to produce energy. This can be impaired by a reduced blood supply, so oxygen cannot get to the areas it needs to, like the spinal cord. A lack of oxygen supply is called hypoxia and is prevalent in diseases such as ALS/MND, where diaphragm weakness can cause intermittent bouts of hypoxia in people with the disease. Thus, protection against hypoxic insults may be important for brain cell survival.

      By using a mouse model of MND, which was engineered to produce a mutant version of SOD1, which causes MND, the researchers from the Kyoto University in Japan aimed to use a compound that they identified in a previous unreleased study, called 6-Deoxyjacareubin. 6-Deoxyjacareubin is a naturally occurring compound which the researchers used to alter the way that hypoxic signalling occurred to reduce motor neuron death.

      The results of this study showed that by administering 6-deoxyjacareubin, to the MND mice, their survival time was increased significantly, by around 16 days, and there was also a tendency towards the delay of onset in the mice. They also found that there was recovery in the number of motor neurons as 6-deoxyjacareubin protected them from hypoxia-induced cell death. They also found an increase in the number of activated glial cells in the control mice. Glial cells are the supportive cells of the central nervous system and an example of their function is to provide nutrients to neurons. An increase in the number of glial cells, could increase the number of chemical signals leading to abnormal levels of inflammation which can exacerbate the disease.

      Overall the results showed that this compound, 6-Deoxyjacareubin, could present as a potential therapy for MND, as it is suggested to inhibit hypoxia-induced cell death. This inhibition could also prove useful for other diseases that are characterised by hypoxia, including Alzheimer’s Disease and Parkinson’s Disease.

      To read the full article please click here

      June MND Research Article summary – Ben Hall, PhD student, University of Sheffield

      Ben Hall, a PhD student at the University of Sheffield kindly provided a lay summary for an MND research article recently published.

        Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72 (13/04/2020; doi: 10.1038/s41593-020-0619-5)

      One of the major causes of ALS/MND is a mutation in a gene known as C9ORF72, which is present in around 10% of patients, and is toxic to the cells of people with the mutation. In a healthy individual the C9ORF72 gene would ordinarily provide a template for the cell to engineer a protein that carries out several roles in a cell. Mutation in the C9ORF72 gene can cause toxicity to a cell in two ways. It can cause a toxic ‘gain of function’ in which the template provided by the gene engineers a protein whose function is altered in a way that is detrimental to the cell, thus causing toxicity. Alternatively, the mutation could prevent the protein from carrying out its usual function also causing toxicity. The exact mechanism, whether it be via a gain or loss of function of the C9ORF72 protein is currently unknown.

      In a study by Zhu et al., (2020), the researchers set out to investigate the mechanism via which a C9ORF72 mutation can cause toxicity. To do this they used gene editing techniques to ‘inactivate’ the C9ORF72 gene in mouse models that had the MND causing mutation. They found that inactivating the mutated C9ORF72 gene accelerated death in these mice that also had a reduced ability to perform normal movement and demonstrate cognitive ability (the mice were tested on their ability to complete a maze). These mice also showed increased motor neuron death, coinciding with an increase in activation of astrocytes and microglia (cells that provide a supporting role to motor neurons and become ‘activated’ in response to neuron damage). The mutation also caused a reduction in levels of autophagy (a cellular process that removes malfunctioning proteins).

      These findings allowed the researchers to conclude that the C9ORF72 gene may cause motor neuron death through a loss of protein function AND a gain of function, an important finding in the search for effective MND treatments. This evidence demonstrated in the study also supports the hypothesis for an ongoing phase 1 clinical trial, potentially benefiting patients within years.

      To access the full article please click here

      Sheffield Biomedical Research Centre (BRC)

      One of the main aims of the SMND RAG is to assist researchers by reviewing research study documentation ensuring that patients and carer’s views are considered. The National Institute for Health Research (NIHR) Sheffield Biomedical Research Centre (BRC) is a research partnership between the University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, dedicated to improving the treatment and care of people living with chronic neurological disorders and the group have assisted in reviewing a number of MND projects for them.

      Sheffield Biomedical Research Centre (BRC) website

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