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June 2021

An open letter to MND researchers

Attached is a letter to MND researchers from a patient with motor neurone disease, which I invite you to take a few moments to read and consider.

The letter is written from a patient who has been a valued member of the SMND RAG until recently, when he took the difficult decision to step back from the group due to his deteriorating speech and finding it difficult to communicate.  The thing he really enjoyed as a member was having interactions with researchers and other members of the group, which was becoming increasingly difficult and frustrating for him, and he didn’t feel he would get the same enjoyment by providing written feedback.

When he got in touch to let me know he was stepping down, he included “a final thought to MND researchers”, which I found incredibly inspiring and motivating.  At the end of what had felt like a tough work day – it put things in perspective and reminded me what I love about my job, and made me want to give that bit more to do everything I can to drive research forwards …

The open letter is written to all MND researchers – a call-to-arms, if you like – to be shared far-and-wide.  I hope that you can take a few minutes to pause and consider how important your research is, and that his powerful words inspire and motivate you to drive your research forwards as far and as fast as you can.

Please do share it with your colleagues – clinical and lab-based MND researchers, technicians, admin, managers, all other support roles… we are all essential to making meaningful progress to translate into patient benefits.

Very best wishes, Stacy Young, Chair of the SMND RAG

May 2021

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

February 2021

February 2021 MND Research Article summary – Amy Keerie PhD student, University of Sheffield

Lessons learnt from a new C9orf72 mouse model of ALS

Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs.

Nguyen et al. 2020. https://doi.org/10.1016/j.neuron.2020.09.009
Liu et al. 2016. http://dx.doi.org/10.1016/j.neuron.2016.04.005
Mordes et al. 2020. https://doi.org/10.1016/j.neuron.2020.08.009

Animal models are important in scientific research as they allow us to better understand diseases and enable testing of potential therapeutic drugs. Mouse models are usually based on genetic changes found in humans who have the disease. For amyotrophic lateral sclerosis (ALS), the “gold standard” mouse model is the SOD1G93A mouse model, which is based on a specific mutation in the human SOD1 gene. This was the first mouse model for ALS and is still widely used today. These mice get progressive ALS symptoms including motor neuron loss and paralysis, however, research has shown that that drugs which show positive results in these mice often fail to translate to humans when they are taken to clinical trials. The cause of this discrepancy could be due to a variety of reasons, such as how the studies in mice were conducted. However, SOD1 mutations only account for a small proportion of ALS cases, so this original mouse model may only be representative of SOD1-specific ALS. As more ALS genes have been identified in patients over time, more animal models have been created which may better represent ALS patients, and therefore could aid with understanding the disease and finding effective treatments.

The most common genetic cause of ALS is the alteration of the C9orf72 gene and this paper discusses a mouse model that was created with a mutation of this gene. Different groups of researchers have created C9orf72 mutant mice, but only one of these (described in Liu et al., 2016) has symptoms of ALS such as motor neuron loss, paralysis and decreased lifespan compared to normal wild type (i.e. non-mutated) mice. One interesting feature of these mutant mice was that there was variability in disease severity, where some mice developed symptoms of disease rapidly, others more slowly, and others not at all. In 2017, these mice were shared with other researchers in the wider scientific community so that more research could be conducted with this model. Recently, a paper was published by Mordes et al., 2020 stating that the mice they had obtained did not show motor neuron loss, paralysis or a decreased lifespan.

The paper highlighted (Nguyen et al., 2020) is by the authors of the original 2016 paper and they back up their original findings regarding the symptoms in the mutant mice with more data from their own and from other laboratories. They suggest that differences in mouse breeding regimes, experimental design and data collection may be the reason that other research groups are not observing symptoms of ALS in the mouse model. Some of the reasons outlined for the differences seen in the symptoms are:

  • Use of different background strains of mice. This can be thought of as the “ethnicity” of mice and it introduces different genetic factors that cannot be controlled for.
  • The number of mice used for analysis.
  • Whether the mice were split into fast and slow disease progressors for some types of analysis.
  • The frequency of data collection. Sudden changes can be missed if the time points are too spread out.
  • The environmental conditions in each laboratory. Things like the food given, pH of water and bacteria present may affect the mice.

All of these factors need to be investigated further. This debate about how accurately the C9orf72 mouse models ALS is really important and highlights some of the limitations of using animal models for disease. Models need to be robust and reproducible, so standard protocols need to be adopted by different research laboratories around the world in order to gain a better understanding of ALS and develop treatments.

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.

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