Tofersen: antisense oligonucleotide drug shows promising results in Phase 1/2 trial

A recent press release by the pharmaceutical company Biogen reported preliminary results from an ongoing clinical trial investigating a form of precision therapy in people with SOD1-related MND. This drug, known as tofersen, is now in the final stages of Phase 1/2 testing in centres across the world, including Sheffield in the UK.

Tofersen is an antisense oligonucleotide (ASO), designed to prevent the faulty disease-causing protein from being made. Proteins, the building blocks of the body, are created from our genetic information (DNA) via its photocopy (RNA). If a piece of DNA is damaged, the RNA will also be damaged, leading to formation of a faulty protein and creating issues in the body. Tofersen is a synthetically-created RNA directed to stick to the faulty photocopy (RNA) preventing it from making faulty proteins.Read More »

The effects of ashwagandha in a SOD1 mouse model of MND

The research team frequently gets asked about the effectiveness of alternative therapies and their use as treatments for MND. Here we report on a recent paper that looked at the effects of ashwagandha, or Indian ginseng, in a SOD1 mouse model of MND.

For around 3000 years Withania somnifera (WS), commonly known as ashwagandha or Indian ginseng, has been used in Ayurvedic and indigenous medicine around the world, and is thought to have powerful rejuvenating and life-prolonging qualities. But there is increasing evidence which suggests that the plant extracts (root, leaf or fruit) also have neuroprotective properties, and this has been demonstrated in several models of neurodegenerative diseases including MND.Read More »

Steps to understanding MND

Love them or loath them, the band Steps’ first single ‘5,6,7,8’ was a techno line dance song released in 1998 from their debut album ‘step one’, with the B side ‘words of wisdom’.

Using this forced and purely tenuous link and an equally awkward segue, I would like to share with you the news that the journal Neurology this week published further words of wisdom from Professor Adriano Chio, Professor Ammar Al-Chalabi and colleagues, that revisits the multistep hypothesis of MND. Their previous work showed that when no genetic cause is considered, developing MND is a six-step process. In their most recent work, the team investigated how many of the steps does a genetic mutation account for in this multistep process, with a focus on the most common MND causative genes SOD1, TARDBP, and C9ORF72.Read More »

New urine-based biomarker opens a gate to improved tracking of MND

Researchers from the Flinders University, Australia and University of Miami have discovered a new protein that can act as a biomarker to track disease progression in people with MND. A paper written under the leadership of Dr Shepheard and Dr Rogers was published today in the research journal ‘Neurology’.

What is p75 and what do we know so far

mndassociationgeneral3The biomarker is a protein called p75, which initially
supports the growth of neurones during embryonic development and its levels markedly decrease after birth. Throughout our lives, p75 only reappears in higher levels when the body detects injury of the nervous system, and shows its presence in urine.

The researchers have previously shown that, after birth, mice with a mutation in the SOD1 gene, known to cause MND, had high levels of p75 after about 40 days from the onset of MND. This also coincided with increased levels of p75 in motor neurones found in tissue of people with MND after death.

Read More »

SOD1 Stuff

With all the talk of new gene discoveries in recent years, the Sunday morning scientific session returned to the original discovery in 1993 that mutations in the SOD1 gene were responsible for around a fifth of familial (inherited) MND cases and 2-3% of all cases of the disease.

Although much of our understanding of MND in the past two decades comes from SOD1 laboratory models of the disease, we still don’t know exactly how SOD1 kills motor neurons. But that hasn’t stopped several groups from working on a number of innovative ways of protecting motor neurons from SOD1 toxicity. Although focused on a relatively rare form of MND, some of the strategies being followed could potentially also be applicable to other forms of the disease.

sod1 stuctureRead More »

Sheffield work towards a treatment for SOD1 form of MND

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.

Laboratory PhotoThe research

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 »

Genetic testing – guidelines needed suggest researchers

The 24th International Symposium on ALS/MND began in Milan today with a record number of over 950 delegates attending to hear the latest news in MND research.

Inherited MND is a rare form of MND characterised by a family history of the disease. Over recent years more and more genes have been discovered, which has lead to an increase in individuals wishing to pursue genetic testing.

Read more about inherited MND on our website

A genetic test consists of a sample, which is then sent off to a genetic laboratory. Here the blood sample is then screened for the MND-causing genes.

The gene that is faulty in inherited MND can differ between one affected family and another. Mistakes in genes called SOD1, TARD-BP, FUS and C9ORF72 between them account for about 65 – 70% of cases of inherited MND. Scientists have yet to identify the gene defects that cause the remaining 30%.

Read More »

Same disease.. two very different mice!

The exact course, duration and rate of progression of MND often varies greatly from person to person; even when there is a known family history of the disease caused by a specific MND-causing gene (eg SOD1).

This same variability also occurs in mice. Researchers, funded by the MND Association, took two mice with the same SOD1 gene mutation from two different families (strains). By using these two mice the researchers identified a number of key changes in motor neurones that differ between fast and slow progressing forms of the disease.

Two mice… One gene

The SOD1 mouse
The SOD1 mouse model has been one of the most important MND research tools for scientists

Developing new disease models enables us to both understand the causes of MND and test potential new therapies.

Mice are commonly used in MND research and for the past 10 years or more, the SOD1 mouse model has been one of the most important research tools for scientists working in the field, particularly with testing potential new therapies.

Research published in September 2013 was carried out in a joint collaboration between Dr Caterina Bendotti (Mario Negri Institute for Pharmacological Research, Milan Italy) and Prof Pam Shaw (University of Sheffield, UK).

Read More »

A PERK for neurodegenerative disease?

Our bodies need to be able to make new proteins, to maintain long term memory. So if the ability to make new proteins is switched off, does this cause Alzheimer’s Disease? New research findings published yesterday by scientists based in Leicester take us closer to answering this question. Journalist are describing this as a step forward for all neurodegenerative disease, so I wanted to explain what the researchers found, and what it might mean for MND.

What’s the story?

The activated form of a chemical called ‘eIF2’, is found in higher levels than normal in the brains of Alzheimer’s Disease patients. (In it’s turn, eIF2 is activated by an enzyme called PERK – hence the name of the blog post.. !).

Last month (September 2013) researchers found that genetically blocking the activation eIF2 prevented memory problems in a mouse model of Alzheimer’s Disease. The research published yesterday showed that in a mouse model of prion disease, chemically blocking eIF2 (as opposed to genetically blocking it) helped prevent the development of prion disease (Variant CJD or ‘mad cow disease’ is an example of a prion disease).

The chemical block was given to mice orally (one of way of doing this is to give it to them in their food). It got to the brain OK and effectively blocked eIF2, but the chemical did have serious side effects. So it’s a possible turning point for drug treatment for Alzheimer’s Disease and prion disease, but not the answer.

Read More »

The not so powerful omega-3

Omega-3 fatty acids have been in the media a great deal over recent years. They can lower our risk of heart disease and they may even have neuroprotective properties (for example limit damage to the brain and spinal cord after acute injuries).

But, what about in MND? Could this dietary supplement have an effect?

MND Association-funded researchers have found out, rather unexpectedly, that the omega-3 fatty acid eicosapentaenoic acid (EPA) actually accelerates disease progression in an animal model of MND which is based on a SOD1 mutation, when EPA is given before symptoms first appear (this is sometimes known as the pre-symptomatic stage).

Why omega-3 might have had an effect

Omega-3 polyunsaturated fatty acids are natural compounds primarily found in oily fish such as sardines, mackerel or salmon. They have been widely associated with significant health benefits and researchers have reported that some long-chain polyunsaturated fatty acids may be beneficial in several neurological conditions.


Previous research in rats has shown that dietary food supplements, containing omega-3 long-chain polyunsaturated fatty acids (including EPA), reversed age-related problems in neurones (nerve cells) and also enabled the growth of new neurons.

The neuroprotective properties of EPA could occur through a variety of mechanisms such as reducing oxidative stress (damage due to low oxygen levels), reducing neuroinflammation  and the activation of anti-‘cell death’ pathways. These are all factors that are relevant in MND.

A number of studies have found that high blood lipids (the breakdown product of dietary fats) are a common feature in ALS (the commonest form of MND), and are correlated with increased survival. High-fat diets have been studied in the lab to further investigate this and have been shown in mice to delay motor neurone death and extend lifespan.

What the researchers found

Due to these previous studies the researchers decided to study one omega-3 long-chain polyunsaturated fatty acid in particular, EPA, to assess whether it had neuroprotective effects in a mouse model of ALS based on a mutation in the enzyme SOD1.

Mouse models are commonly used to study the causes of the disease and investigate potential treatments in MND. A SOD1 mouse model is a mouse that has been given a faulty MND-causing gene producing an enzyme known as ‘SOD1’, which is known to cause 20% of cases of the rare inherited form of MND.

The researchers intended to study the effects of dietary EPA when given at disease onset (the symptomatic stage when symptoms first appear) or at the pre-symptomatic stage.

The mice were fed either a standard rodent powdered diet (control) or a diet supplemented with EPA-enriched oil. The researchers then looked at a number of factors such as: disease progression, survival and body weight to find out if there were any differences.


When a diet supplemented with EPA was given at the symptomatic stage there was no significant difference in the development of MND compared to the control group (mice who were fed a standard rodent powdered diet). However, rather unexpectedly, when the EPA diet was given at the pre-symptomatic stage, the researchers found that the diet accelerated the progression of MND, but did not affect disease onset.

Glial cells (such as astrocytes and microglia) were also affected, and found in reduced levels when the mice were given the EPA diet.

Overall, the researchers found that long-chain omega-3 fatty acid EPA-enriched diets have no impact on disease onset or survival. Unexpectedly, if dietary EPA is given before symptoms appear it can actually accelerate the progression of MND.

What this means for people living with MND

The omega-3 fatty acid EPA, although it may have other health benefits, appears to have the potential to be more damaging rather than protective in this specific MND mouse model. The results from this study have highlighted the need for caution by those who are at risk of developing MND, who may use these long-chain omega-3 fatty acids dietary supplements, which are freely available, over prolonged periods of time.

This study has shown that individuals who carry the SOD1 inherited form of MND in particular should take extreme caution with diets enriched in long-chain omega-3 fatty acids such as EPA. For the future, it remains to be seen if EPA has also negative effects in other models of MND (eg zebrafish or flies with the C9orf72 mutation).

Dr Adina Michael-Titus (Blizzard Institute, Queen Mary University of London), one of the researchers involved in the study, commented “The most important point, in my view, is to be aware that we do not have yet the scientific evidence to prove that EPA or any other omega-3 fatty acids are dangerous for all forms of MND. The only experimental evidence we have so far is for a particular SOD1 mutation which leads to this disease (where the faulty SOD1 mutation is greatly overexpressed). More work is required and future research will help us fully assess and understand the potential or the risk associated with omega-3 fatty acids in people living with MND.”

Dr Andrea Malaspina
Dr Andrea Malaspina

Dr Andrea Malaspina (a member of our Biomedical Research Advisory Panel) also commented on the results. “EPA was found to accelerate the progression of MND when given at the pre-symptomatic stage in a SOD1 mouse model. To fully assess the potential risk of EPA further research is needed in other animal models, with different MND mutations (as different mutations cause different metabolic changes) to see if a similar effect is observed. At present we can only say that EPA accelerates the progression of MND in a SOD1 mouse model and it is not known whether it accelerates the progression of all forms of MND.”

For more information about the rare inherited form of MND please see our website

References: Yip PK, Pizzasegola C, Gladman S, Biggio ML, Marino M, et al.  (2013) The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis. PLoS ONE 8(4): e61626. doi:10.1371/journal.pone.0061626