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Target Research Issue 2 of 4 2014

Ask a scientist

Conference report The highlights of the seventh annual neuromuscular transitional research conference


Our guide to how genes are passed on from one generation to the next

Also inside‌ read about all the latest research and clinical trial news from the UK and around the world


Glossary This glossary is intended to help with some of the scientific and technical terms used in this magazine. Words that are in the glossary are highlighted in italics in the text. Animal model – a laboratory animal such as a mouse or rat that is useful for medical research because it has specific characteristics that resemble a human disease or disorder. Biomarker – a biological substance found in blood, urine or other parts of the body that can be used as an indicator of health or disease. A biomarker may be used to help clinicians diagnose a condition and monitor how it is progressing, but can also be used to see how well the body responds to a treatment. DNA – (deoxyribonucleic acid) is the molecule that contains the genetic instructions for the functioning of all known living organisms. DNA is divided into segments called genes. Dystrophin – the protein missing in people with Duchenne muscular dystrophy and reduced in those with Becker muscular dystrophy. Dystrophin is important for maintaining the structure of muscle cells. Embryo – A fertilised egg that has the potential to develop into a foetus. Exon – genes are divided into regions called exons and introns. Exons are the sections of DNA that code for the protein and they are interspersed with introns which are also sometimes called ‘junk DNA’. Exon skipping – a potential therapy currently in clinical trial for Duchenne muscular dystrophy. It involves ‘molecular patches’ or ‘antisense oligonucleotides’ which mask a portion (exon) of a gene and causes the body to ignore or skip over that part of the gene. This restores production of the dystrophin protein, albeit with a piece missing in the middle. Gene – genes are made of DNA and each carries instructions for the production of a specific protein. Genes usually come in pairs, one inherited from each parent. They are passed on from one generation to the next, and are the basic units of inheritance. Any alterations in genes (mutations) can cause inherited disorders. Inflammation – the body’s reaction to injury or infection. It is a protective attempt by the body both to remove whatever is causing the injury or infection (for example a splinter in your finger or a virus in your lungs) and initiate the healing process. mdx mouse – a mouse model of Duchenne muscular dystrophy. These mice have a mutation in the dystrophin gene – the gene that is mutated in boys with Duchenne muscular dystrophy. The muscles of these mice have many features in common with the muscles of boys with this condition. Membrane – the barrier between the inside and outside of a cell or between two compartments of a cell. Membranes act like a skin to protect cells and control which substances leave or enter them. Molecular patch – a short piece of genetic material (DNA or RNA) which can bind to a specific gene and change how the code is read. Also called an ‘antisense oligonucleotide’.

Mouse model – see animal model. Mutation – a permanent change in the DNA code that makes up a gene. Depending on where the mutation occurs, and the type of mutation, they can either have no effect or result in genetic diseases such as muscular dystrophy. Mutations can be passed on from generation to generation. Next generation sequencing – a cutting-edge technology that allows researchers to ‘read’ the whole of an individual’s genome. Researchers have recently started to use it for finding new genes and diagnosing genetic conditions more accurately. Nucleus – the control centre of a cell, which contains the cell’s chromosomal DNA. Phase 1 clinical trial – a small study designed to assess the safety of a new treatment and how well it’s tolerated, often using healthy volunteers. Phase 2 clinical trial – a study to test the effectiveness of a treatment on a larger number of patients. Participants are usually divided into groups to receive different doses or a placebo. Phase 3 clinical trial – a multi-centre trial involving a large number of patients, aimed at being the definitive assessment of how effective a treatment is prior to applying to the regulatory authorities for approval to make the treatment widely available. Placebo – an inactive substance designed to resemble the drug being tested. It is used to rule out any benefits a drug might exhibit because the recipients believe they are taking it. Protein – molecules required for the structure, function and regulation of the body’s cells, tissues and organs. Our bodies contain millions of different proteins, each with unique functions. The instructions for their construction are contained in our genes. Randomised controlled trial – a clinical trial where treatments and placebo are allocated randomly to participants rather than by conscious decisions of clinicians or patients. SMN protein (Survival Motor Neuron protein) – produced by the SMN genes and reduced in individuals with spinal muscular atrophy. This protein is necessary for normal motor neuron function. Stem cells – cells that have not yet specialised to form a particular cell type, and can become other types of cell such as muscle cells. They are present in embryos (embryonic stem cells) and in small numbers in many adult organs and tissues, including muscle. Translational research – the application of knowledge gained from scientific medical research in the laboratory to studies in humans. Utrophin – a protein very similar to dystrophin. Low levels of utrophin are present in everyone – including people with Duchenne muscular dystrophy – but in insufficient amounts to compensate for the loss of dystrophin.

About us The Muscular Dystrophy Campaign is the leading UK charity fighting muscle-wasting conditions. We are dedicated to beating muscular dystrophy and related neuromuscular conditions by finding treatments and cures and to improving the lives of everyone affected by them. The Muscular Dystrophy Campaign’s medical research programme has an international reputation for excellence, investing more than £1m each year, which includes more than 25 live projects taking place at any one time. Our information, care and support services, support networks and advocacy programmes support more than 5,000 families across the UK each year. We have awarded more than 6,000 grants totalling more than £6m towards specialist equipment, such as powered wheelchairs.

References and further information Please contact us at if you would like any further information or a link to the original research article. The articles are written in technical language with no summary in layman’s terms; and some may require a payment before they can be viewed.

Disclaimer While every effort has been made to ensure the information contained within Target Research is accurate, the Muscular Dystrophy Campaign accepts no responsibility or liability where errors or omissions are made. The views expressed in this magazine are not necessarily those of the charity. ISSN 1663-4538

Muscular Dystrophy Campaign, 61A Great Suffolk Street, London SE1 0BU t: 020 7803 2862 e: w: Registered Charity No. 205395 and Registered Scottish Charity No. SC039445 Printed on PEFC paper, produced at a mill that is certified with the ISO14001 environmental management standard. Enclosed into a bio-degradeable polybag



Welcome to the second edition of Target Research for 2014! Before I go any further, I’d like to draw your attention to the survey you will have received with the magazine. We like our communications to give you the information you would like in a way you would like it. If you could take a few minutes to complete the survey to give us feedback for both Target MD and Target Research and post it back using the freepost address, it’ll be a great help in improving what we do. In this issue we take a closer look at genetics and inheritance. Most of the conditions the charity supports are genetic, and this article aims to explain how inheritance works within families and how genes and mutations are passed from parents to children. We also have a conference report from the recent Translation Research Conference held in London. The event attracts scientists from around the world who present talks and posters. This is a great chance for us to catch up on the latest research and talk to the researchers themselves and here we present our highlights of the conference. I do hope you enjoy this edition of Target Research. And if you could spare a few minutes to complete our survey, I would really appreciate that.

Neil Bennett Editor t: 020 7803 4813 e: tw: @ResearchMDC

Contents 4

Genetics and inheritance A guide to how genes are passed from parents to children


Research news A round-up of news stories from around the world

11 The importance of partnerships Dr Marita Pohlschmidt, Director of Research 12 Conference report A report from the annual Neuromuscular Translational Research conference 14 Ask a Scientist Your questions answered

Follow us on: Follow us on: leading the way forward


A guide to inheritance and genetics Genes make us who and what we are. They define our eye colour, hair colour, blood group and susceptibility to disease. They are passed from parents to children down the generations and some people say that genes are the code to life itself. We have approximately 23,000 genes and each one carries the blueprint to make a protein our cells require for a specific function. Damage to a gene can affect the production of its protein and this in turn can lead to a genetic condition. There are over 6,000 genetic conditions known in humans and we support people affected by just 60 of these. One of the key aspects of all genetic conditions is that the damaged gene - and therefore the condition - can be inherited, or passed from parents to children. It is important for families to understand how inheritance works so they can make informed choices about family planning, and in this article we will explain the most common routes of genetic inheritance.

CHROMOSOMES, DNA AND GENES The differences between chromosomes, DNA and genes can often seem confusing, but this short guide may help: DNA is the biological molecule that conveys genetic information inside cells. In our cells, DNA is organised into genes. Genes carry the blueprint cells need to produce a single protein. Humans have approximately 23,000 genes, with two copies of each. Genes are made of DNA and held together in structures called chromosomes. Chromosomes are the structures where DNA is stored. Humans have 23 pairs of chromosomes and children inherit one of each pair from each parent. One pair of chromosomes (called X and Y) define the gender of an individual. One way to think of this is as a small library with 46 books (chromosomes), each made up of many sentences (genes) in turn are formed of words and letters (DNA).

What causes genetic conditions? Researchers estimate that there could be up to 10,000 differences in the DNA of any two individuals (see DNA code). These differences arise naturally over time and the majority are harmless spelling variants – maybe like fibre or fiber (depending on whether you learnt English in the United Kingdom or United States of America) – which are thought to have no effect on the genetic blueprint carried by the gene. Some of the changes in the DNA do have an effect


THE DNA “CODE” The DNA which forms a gene contains long chains of individual units joined together – like letters forming a sentence. These units are called bases and the human genome contains around three billion in total! There are four different types: adenine, cytosine, guanine and thymine (or A, C, G and T for short). These letters can spell out a message giving a cell precise instructions to produce a protein. Proteins are built from components called amino acids which must be arranged in the correct order for a protein to function properly. However, there are at least 20 amino acids and one of the challenges for researchers was to work out how messages made up of just four letters could distinguish between 20 amino acids. In the 1960s researchers showed that DNA holds the information in a code called the “triplet code”, where three letters in the DNA are used to identify each amino acid. Although codes are often thought of as secret ways to send messages, they can also be used to send information in the minimum amount of space. For instance, at the Battle of Trafalgar, Admiral Nelson sent a now famous signal “ENGLAND EXPECTS THAT EVERY MAN WILL DO HIS DUTY” to his fleet. If each word needed had to be spelt, the crew of HMS Victory would have needed to hoist 61 flags (one for each letter) – something they didn’t have time to do. Luckily they had a code book. This was not a secret book, but a book that translated certain words (like England) into signals using just three flags. This meant the message was could be sent using just 31 flags.

on the genetic blueprint – and protein production – and these changes are called mutations. There are many different types of mutation: bases in the DNA can be changed (for example a T changed to an A) or added or deleted. Mutations may be as small as one changed or deleted bases in the DNA; on the other hand, mutations have been reported where tens of thousands of bases are deleted. Because the DNA is read in triplets,

tiny mutations which alter these triplets can have a large effect. If we imagine a gene is a sentence of three letter words: The man and his dog ran for the bus Adding just a single letter can move all the triplets along one place and destroy the meaning of the whole sentence (although the message is still present if you look carefully!):

in an individual, mutations can also be inherited by an individual’s children and understanding this process is crucial for individuals and couples wanting to make informed choices about family planning. In the next pages we explain how mutations are inherited.

The Xma nan dhi sdo gra nfo rth ebu s As well as causing a genetic condition leading the way forward


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X-linked inheritance

Autosomal recessive

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Humans have 46 chromosomes arranged in 23 pairs and children inherit one of each pair from each parent. It is therefore possible to draw diagrams (see above) to show the relative likelyhood of inheriting a mutation depending on its type and location. There are 3 main modes of inheritance that we will cover: X-linked, autosomal inheritance (including recessive and dominant) as well as mitochondrial inheritance which has some important differences.

X-linked inheritance Humans have one pair of chromosomes which vary between males and females. These chromosomes are called X and Y; males have one X chromosome and one Y chromosome while females have two copies of the X chromosome. Just like the other chromosomes in our cells, mutations in these chromosome can cause genetic conditions. Because females have two X chromosomes, while males have only one, these conditions mainly affect males – a mutation in the single copy of a gene can cause the condition. For a female to have an X-linked condition, mutations would have to be present in each of two copies of the gene (one on each X chromosome) and this is very rare. However, females can be carriers. Carriers have one copy of the mutated gene and one healthy copy and do not usually experience symptoms except in rare cases (see manifesting carriers). The diagram above shows that one in two sons born to a carrier mother with an X-linked condition will themselves have the condition. When a father with an X-linked condition has children, all daughters will be carriers (since they inherit the mutated copy of the gene on his X chromosome) while sons will be healty because they inherit their father’s Y chromosome.

MANIFESTING CARRIER Duchenne muscular dystrophy is caused by mutations in the dystrophin gene which is located on the X chromosome (see X-linked inheritance) and the condition mainly affects males. However, a female can be a carrier of the condition if one copy of her dystrophin genes is mutated. Usually carriers of a condition do not show any signs or symptoms, but in Duchenne muscular dystrophy approximately ten percent of carriers may be very mildly affected (often without realising), with enlarged calf muscles. In approximately five percent of carriers, careful clinical testing can sometimes show some weakness in the muscles of the shoulders and hips and in less than one percent of cases, the individual may have muscle weakness that means they need to use a wheelchair. Whilst it is very rare for a carrier to have symptoms as severe as a boy or man with Duchenne muscular dystrophy, some carriers experience some mild heart problems. Clinicians recommend that carriers receive screening for these issues, because drug treatment can be helpful for some individuals. Researchers have suggested various reasons why some carriers experience symptoms but this area is still not well understood. However, clinicians and researchers are currently investigating this and we will keep you updated with any results.

Autosomal dominant

Mitochondrial inheritance


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Autosomal inheritance The chromosomes other than those which define gender are called autosomes (hence autosomal inheritance). Humans have 22 pairs of autosomes and each member of a pair is identical, so each cell has two copies of each gene. When a gene is mutated, the second copy of the gene is often able to produce enough protein to compensate for the mutated copy. In this case the mutation is said to be recessive. However, in some cases, a single mutated copy of a gene can overcome its partner (often because a protein with a new, damaging function is produced) and the mutation is said to be dominant. There are therefore two types of autosomal inheritance: autosomal recessive (where the the mutated gene is said to be recessive) and autosomal dominant (where the mutated gene is said to be dominant). It must be noted that some conditions can be caused by both dominant or recessive mutations. The only way to know how a mutation is likely to be inherited is for clinicians to perform genetic testing – something we will cover in a future issue of Target Research.

Autosomal recessive Any parent who is a carrier of an autosomal recessive condition can pass on either the healthy copy of the gene or the mutated copy and the diagram above illustrates the possible patterns of inheritance. If one parent is a carrier, then there is a one in two chance that the child will also be a carrier. Where both parents are carriers there are are four possibilities: The first is that a child will inherit the healthy gene from both parents and will neither have the condition nor be a carrier.











The next possibility is that the child can inherit one healthy copy and one mutated copy of the gene and will be a carrier. The final possibility is that the child will inherit a mutation from both parents and have the condition. A child of parents who are both carriers has a one in four chance of inheriting two usual forms of the gene, a one in two probability of being a carrier and a one in four probability of inheriting the condition.

Autosomal dominant Since a single copy of the mutated gene will always cause the condition, it is not possible to be a carrier of a dominant mutation. If one parent has a genetic condition caused by a dominant mutation, there is therefore a one in two chance that the child will also have the condition and if both parents have the condition all the children will have the condition.

Mitochondrial inheritance As well as the genes found on chromosomes in the nucleus, there is a very small number of genes (eleven) in the mitochondria which are the small structures which provide energy for the cell from the food we eat. The mitochondrial genes are needed only for energy production and mutations in these genes can cause a range of conditions including mitochondrial myopathy. The genes in mitochondria are inherited in a totally different manner from the genes in the nucleus. Mitochondrial DNA is inherited only from the mother. This means that if a mother has a mitochondrial disease, all her children will have the condition; conversely, a father with mitochondrial disease would have healthy children. leading the way forward


News Research

The research team is always on the look-out for exciting developments in the field of muscular dystrophies and related neuromuscular conditions. Here we bring you the latest research and clinical trial news from around the world.

New genetic mutations discovered that cause myopathy in children Two new genetic mutations have been discovered that cause myopathy. The mutations are in a gene called MICU1, which carries instructions for a protein with the same name that is essential for mitochondrial function. This is the first time that mutations in the MICU1 gene have been linked to myopathy and the discovery gives us a better understanding of the genetic causes of the condition. This will lead to more patients receiving an accurate diagnosis in the future and could highlight potential targets for future therapies. An international team of researchers from the UK, the Netherlands and Italy, including Muscular Dystrophy Campaign-funded Professors Michael Duchen and Francesco Muntoni, has identified new mutations that cause a childhood disorder that typically involves muscle weakness, movement problems and learning difficulties. The researchers used a technique called exome sequencing to analyse the genes of 15 people with this condition and found two different mutations in a gene that contains instructions for a protein called MICU1, which is essential for mitochondrial function. Mitochondria are the batteries of the cell where energy is produced. They are found in large numbers in nerve and muscle cells, which have high energy demands. To function correctly, mitochondria need a certain amount of calcium. If calcium levels are either too high or too low, they stop working properly. The calcium level in the mitochondria is controlled by many proteins, including MICU1. Mutations in the MICU1 gene caused less MICU1 protein to be produced which led to an increase in calcium in the mitochondria. This resulted in damage to the mitochondria and changes in calcium levels in the rest of the cell. Professor Duchen said about the research: “Mitochondrial calcium signalling has long been thought to be important in regulating cellular energy supply, and defects in these pathways have been thought to be important in many diseases. However, this is the first time that a human condition has been directly linked to a gene defect in this pathway, so this is very exciting for us.” This research has revealed two new mutations that can cause myopathy. Although it will need to be confirmed, this might be a new type of myopathy, characterised by complex symptoms including muscle weakness, movement problems and learning difficulties. Both the mutations causing the condition are in the MICU1 gene, which is important in mitochondrial function. Identifying the mutation will lead to more individuals obtaining a precise genetic diagnosis in the future. This can help people to make better-informed family planning decisions and allow clinicians to give more accurate information on how the condition might progress. This can help people plan for the future and gain access to appropriate care. In the longer term, a greater understanding of the cause of myopathy and the genes and proteins that cause it may reveal potential targets for the development of future therapies.

Drisapersen update In September last year, Glaxosmithkline (GSK) announced that a Phase 3 trial of drisapersen – a molecular patch for exon 51 of the dystrophin gene – had failed to show the drug was effective in boys with Duchenne muscular dystrophy. Following that announcement, the company said they would analyse the data more comprehensively to investigate whether drisapersen was effective in a sub-group of the boys who participated in the trial. In a press release, GSK announced that Prosensa – the Dutch biotech company who originally developed drisapersen – had regained the commercial rights to the drug. Prosensa will now continue the review of the drisapersen data. In a separate press release, Prosensa gave preliminary results of the data review that may suggest that some groups of boys could benefit from eteplirsen treatment. In a letter sent to patient advocacy groups including the Muscular Dystrophy Campaign, Prosensa also gave a further update about drisapersen. Following the announcement of the trial results, boys in other, ongoing trials of drisapersen stopped receiving the potential drug but continued to be monitored and to attend follow-up appointments, while a complete analysis of the data was undertaken by the companies. Prosensa has now announced that to minimise the burden on families involved in these trials, they will close (or end) the largest of the ongoing extension trials. The company will keep two smaller trials open but boys in these trials will not receive drisapersen. However, the company continues to review the drisapersen trial data and if they identify individuals or groups who may benefit, then dosing may restart.


Understanding spinal muscular atrophy – how Schwann cells support nerve cells Muscular Dystrophy Campaign-funded researchers led by Professor Thomas Gillingwater at Edinburgh University have made significant discoveries about how spinal muscular atrophy (SMA) develops and the role of Schwann cells in this process. They found differences between Schwann cells from mouse models of spinal muscular atrophy (SMA) and those from healthy mice. Schwann cells from mouse models of SMA do not develop properly and were unable to give nerve cells grown in the laboratory the support they required to survive and function properly. This demonstrates the importance of Schwann cells in SMA and could highlight potential new therapeutic targets for the condition. Schwann cells are vital for nerve cell function. Nerve cells communicate with each other using electrical signals sent down parts of the cells called axons. In the same way that electrical cable is insulated with a plastic sheath, the axons of nerve cells are insulated with a protein called myelin. This is provided by Schwann cells. Schwann cells also support nerve cells by producing proteins for the extracellular matrix, which provides structural and biochemical support for surrounding cells. In these ways, Schwann cells provide essential support for nerve cells. Professor Gillingwater and Dr Hunter investigated these functions using mouse models of SMA and found important differences between Schwann cells

from the mouse models and those from healthy mice. Schwann cells from SMA mice did not respond normally to factors that promote their development; they did not mature into fully functional cells and produced less myelin protein than healthy cells. To test whether they were capable of supporting nerve cells, Schwann cells from SMA mice were grown in the laboratory alongside healthy nerve cells. The nerve cells had thinner myelin insulation and were fewer in number. The extracellular matrix (a mesh of proteins built around our cells) provides essential support for nerve cells and is altered in SMA. Schwann cells play an important role in establishing the extracellular matrix by producing proteins that are incorporated into it, so Professor Gillingwater and his team tested whether this function was compromised in SMA. They found that Schwann cells from SMA mice also produced less of a protein that is essential for formation of the extracellular matrix than their healthy counterparts. This research is important because it increases our understanding of how SMA develops. It shows that Schwann cells are unable to develop into fully functional cells in mouse models of SMA and that this compromises the function of nerve cells. This information could reveal new potential targets for developing therapies and suggests that, once treatments are available, starting treatment of the condition in its early stages will be the most effective strategy.

Ataluren not given conditional approval for Duchenne muscular dystrophy The Muscular Dystrophy Campaign’s Director of Research, The European Medicines Agency has announced that ataluren has not been granted conditional approval to treat Duchenne muscular dystrophy. PTC Therapeutics, the company which developed ataluren, applied for conditional approval late in 2012. The company presented to the regulators data from pre-clinical testing as well as the results of a large phase 2 clinical trial which included 174 boys with Duchenne muscular dystrophy. However, the regulators were not convinced that the results of the clinical trial were sufficiently robust to allow conditional approval of potential treatment at the time. Conditional approval would have meant that ataluren was placed on the market for one year, with provision for yearly renewal. The company would have monitored the safety and effectiveness of the treatment while committing to provide additional study data – for example the results of the phase 3 trial PTC has already started – to confirm the results. PTC has announced that the refusal of a conditional approval by the EMA will not affect the ongoing clinical trials of ataluren, which the company will need to complete in order to apply for full approval of ataluren in the future. If you are participating in a clinical trial of ataluren and have any questions you should ask your clinician.

Dr Marita Pohlschmidt said: “Families will be disappointed by this decision by the EMA not to grant conditional approval for the drug ataluren. There are 200 or more children and young people in the UK who live with Duchenne muscular dystrophy caused by a ‘nonsense mutation’, for whom ataluren may be relevant – 10 to15 percent of the total number affected by the condition. Had the decision been positive, each of them would have had independent access to what appears to be a safe potential treatment for their condition. PTC’s planned phase 3 clinical trial will continue regardless of this decision. However, a conditional licence and extension of the numbers taking the drug beyond those on the trial would have helped the company to develop the evidence base for ataluren more quickly. All those taking the drug would have been closely monitored by health professionals, with the additional data giving PTC a better understanding of how well the drug is working and as a result, a firmer path towards a full, unconditional licence. This news will be a disappointment for everybody racing against the clock to develop treatments that could protect muscles from damage. There are 2,400 children and young people living with this complex condition, and the Muscular Dystrophy Campaign is committed to funding a diverse, peerreviewed and ambitious research programme until effective treatments have been found for every single one of them.

leading the way forward


Hello from Target MD In this edition, we have a special feature on our work in Wales. When I travelled to Wales to meet some of our supporters, I noticed not only the beauty of the countryside, but also the abundance of community. Each person I met had a connection with others and there is a wonderful sense of belonging for newly-diagnosed families seeking support. There are about 3,000 families in Wales affected by muscular dystrophy and related neuromuscular conditions and the dedicated fundraisers and campaigners in our charity community work hard to do what they can to improve the lives of all families affected. In this edition, you’ll meet a marathon-running Welsh Assembly member, several dedicated and longstanding supporters, and some healthcare professionals. The sense of community that comes through is something our online forum, TalkMD, also offers in profusion and Val shares her story of making a new Welsh friend online. As always, we bring you more evidence of our campaigning, advocacy and fundraising successes across the UK and the usual round-up from the Wheelchair Football Association. And please have a look at our #TeamOrange calendar, offering you a huge range of activities to get involved in.

Research news

in brief Would you like to take part in the 100K genome project?

The 100K genome project is a government-funded project to sequence the genomes of a hundred thousand genomes of people in the UK. The project is being organised by Genomics England and its goal is to identify the genes and mutations behind all rare genetic conditions where the cause is currently unknown. The data collected could also help researchers to improve diagnosis and develop new potential treatments. The genome is the collection of all the DNA of an individual and includes all their genes. By sequencing (or reading) all the information in all the genes, researchers may be able to identify mutations which can cause rare genetic conditions. The team at the MRC Centre for Neuromuscular Diseases in London are recruiting people with a neuromuscular condition where the genetic cause is unknown. Participants and at least two close family members will be asked to give a blood sample which will then be used by researchers to sequence the genome. You can find out more about the project from our website and if you are interested in taking part in the project you can contact the MRC Centre for Neuromuscular Diseases in London by email at: or

Eteplirsen update from Sarepta Therapeutics Sarepta Therapeutics has announced in a press release the latest preliminary results of their Phase 2b clinical trial of eteplirsen – a molecular patch designed to skip exon 51 of the dystrophin gene in boys with Duchenne muscular dystrophy.

Ruth Martin Editor, Target MD t: 020 7803 4836 e: tw: @RuthWriter Target MD is also available to read online:

After 120 weeks of treatment, the company said the distance the boys receiving eteplirsen could walk in six minutes was still stable. The company also announced the results of lung function tests as stable, but other measures of muscle function (including the northstar assessment) had declined slightly since the start of the trial. Although this news is encouraging, it must be noted that the trial is very small – with only ten boys in total – and so the results must be viewed with some caution. The boys in the trial will continue to receive eteplirsen, and clinicians will continue to monitor the distance the boys can walk and any side-effects of the potential drug.


Summit starts trial Summit Corporation plc (a biopharma company based in Oxford) has announced that their phase 1b clinical trial of SMT C1100 in boys with Duchenne muscular dystrophy has started. SMT C1100 is designed to increase levels of utrophin in the muscles and researchers and clinicians believe this may compensate for the lack of functional dystrophin observed in Duchenne and Becker muscular dystrophy, regardless of their mutation. This is the first time a drug with the potential to increase utrophin levels has been tested in boys with Duchenne muscular dystrophy. The trial aims to test whether different doses of the potential drug are safe and how well they are tolerated. It will take place at four sites around the UK and researchers aim to recruit 12 boys with Duchenne muscular dystrophy aged between five and 12 who will each receive one of three doses of the potential drug for ten days. As well as monitoring the safety of the boys, clinicians will measure the amount of the drug which enters the bloodstream – a crucial piece of information that will help the company to plan a phase 2 trial which is scheduled to start next year. Depending on the results of the phase 1b trial, Summit has said they aim to start a phase 2 trial ‘with the minimum delay’, possibly later this year. When we find out more details we will let you know.

Call for Duchenne Clinical Research Fellow in Scotland Opens Together with the Chief Scientist Office (CSO) in Scotland and Action Duchenne, we are pleased to announce that a call for a Clinical Research Fellowship in Duchenne muscular dystrophy is now open for applications. This initiative, which is being funded in equal measure by the three organisations, is designed to increase research capacity in Duchenne muscular dystrophy in Scotland. The fellowship is for three years and will cover the salary cost of the fellow and up to £10,000 per annum of research costs. The fellowship is open for individuals currently training in medicine. The successful applicant is likely to be in the speciality phase of their training. The deadline for applications is Monday 30 June 2014. The relevant application form, guidance to applicants and terms and conditions of the award are available from the CSO website. Clinical Research Fellowships can encourage clinicians into an academic research career. They are open to medical graduates, usually during speciality training, and in this case, the fellowship aims to provide an opportunity for further training in specialist laboratory techniques related to Duchenne muscular dystrophy research and relevant clinical expertise.  The Fellowships are ideally placed to promote translational research, the benchto-bedside transfer of promising technology from the laboratory into the clinic. Clinical fellows, with one foot in the laboratory and one foot in the clinic, have a unique opportunity to aid this process; helping the development of potential treatments for Duchenne muscular dystrophy.

Online psychology study opens As reported in the last issue of Target Research, an online questionnaire study examining how psychological factors impact on quality of life and mood over time has been started by researchers based at Edinburgh University. The study, l ed by Dr Christopher Graham, who completed his Muscular Dystrophy Campaign-funded PhD last year and is now training to be a clinical psychologist, could help researchers to develop better ways to support people with muscular dystrophy and related muscle-wasting conditions. The present study takes place completely online and can be done from the comfort of your own home. It will require you to complete two questionnaires; the second questionnaire is completed four months after the first one. If you think that you might be interested in taking part then please read the information on our website at

More than the sum of our parts Just yesterday I was in the Netherlands visiting the European Neuromuscular Centre (ENMC) in Baarn, a small town near Amsterdam. The ENMC was founded in 1992 to encourage communication and collaboration between clinicians and scientists worldwide working in the field of neuromuscular diseases. The organisation offers funding for workshops on topics that the community feels are vital to discuss to move the development of treatments forward. The ENMC is funded nearly exclusively by seven European patient organisations including the Muscular Dystrophy Campaign and represents a powerful example of what partnerships can achieve. The partner charities recognised that the rarity of the conditions makes it essential to create an international platform where experts can share their knowledge and experiences and more than 200 workshops have now taken place. Today, more people get a faster diagnosis, more clinical trials are taking place and there are standards of care for a number of conditions. This would have not happened without the ENMC. The Muscular Dystrophy Campaign has also established partnerships that aim to fund more high quality research through our rigorous peer review system. Last year we established the Duchenne Forum which together committed £850,000 into Duchenne research over the next four years. And we are keen to establish more partnerships with funding institutions, charities, family funds with an interest in investing in high quality research. Because together we can achieve more than the sum of each of us; we can aim high and make the impossible possible.

Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign leading the way forward


Highlights from the seventh UK Neuromuscular Translational Research Conference Exciting new technologies are being used to help diagnose and develop treatments for muscular dystrophy and related neuromuscular conditions. These technologies featured heavily in the programme of the seventh UK Neuromuscular Translational Research Conference that took place at the Institute of Child Health at University College London in March, and which brought together researchers and clinicians from around the UK as well as international speakers. The research team attended the conference and this article looks at our highlights. The UK Neuromuscular Translational Research Conference is co-organised and jointly funded by the Muscular Dystrophy Campaign and the MRC Centre for Neuromuscular Disease and was first held in 2008. The meeting aims to bring together top researchers for presentation and discussion of the latest research – helping to drive forward translational research to develop treatments for muscular dystrophy and related neuromuscular conditions. It is a great opportunity to encourage communication between scientists and clinicians and encourage them to work together and share resources. The conference is held every year in London, Oxford, or Newcastle upon Tyne, and attracts hundreds of scientists, clinicians and industry partners working on neuromuscular conditions. This year, the conference was hosted by the Institute of Child Health at University College London on March 3rd and 4th. The days were jam-packed, with two sessions every day addressing a different topic and creating a platform for researchers to present their latest scientific findings and ideas. There were also more than 75 posters to be discussed over morning coffee and lunch, with experts in the field giving special ‘guided tours’.

Stem cell treatments Researchers from the UK and around Europe came together on the first morning of the conference to present their latest research findings on the potential of stem cells as a possible therapeutic approach for neuromuscular conditions. Encouraging results of recent clinical trials were presented alongside new results showing the potential benefits of stem cell treatments in animal models and new methods to produce large numbers of stem cells.

The highlight of the session was a talk by Professor Gill Butler-Browne from the Institut De Myologie in Paris. She discussed encouraging results from a phase 1 trial testing the safety of stem cell treatment in people with occulopharangeal muscular dystrophy (OPMD). This condition leads to the wasting of small muscles in the head and neck and can cause swallowing difficulty. An effective treatment may only need to restore function to these isolated muscles, so researchers believe that OPMD may be more amenable to stem cell treatments than conditions where all the muscles of the body would need to be treated. With the condition only affecting isolated muscles, the researchers were able to use stem cells from unaffected muscles, reducing the chance of the patient’s immune system interfering with the trial treatment. The trial demonstrated the safety of the technique and also showed that people who received stem cell treatments could swallow better than those who had not received the stem cell treatment.

Protein homeostasis The second session of the conference focused on something called protein homeostasis. This is a collection of different processes which allow cells to maintain the levels of proteins within certain limits – by breaking down existing protein or making new proteins. By learning more about the processes that cells use naturally, researchers hope to develop therapeutic approaches that can artificially stimulate these processes to increase or decrease the level of proteins within the body. Many of the talks in this session were given by experts specialising in fields beyond neuromuscular conditions – a great example of how the conference brings together scientists from different areas to apply exciting new research results to neuromuscular conditions.


The meeting aims to bring together top researchers for presentation and discussion of the latest research – helping to drive translational research to develop treatments.

Magnetic Resonance Imaging The final session of the conference focused on the use of Magnetic Resonance Imaging (MRI) in neuromuscular disorders. MRI could allow clinicians to monitor the progression of neuromuscular conditions non-invasively and the session included preliminary results from several clinical studies which have been taking place around the world. Dr Kieran Hollingsworth from Newcastle University spoke about his group’s work to make MRI faster and cheaper in people with neuromuscular conditions including limb girdle and Becker muscular dystrophy. The new techniques they have developed mean clinicians can now scan in eight minutes what had previously taken half an hour. As well as reducing the time people with neuromuscular conditions might have to spend in an MRI scanner, the researchers also hope that shorter scans could reduce the cost of including MRI as a potential biomarker in future clinical trials. The highlight of the session came from Dr Lee Sweeney who presented preliminary results of the “Imaging DMD study” – a natural history study which aims to use MRI to monitor progression of the condition over five years in 100 boys with Duchenne muscular dystrophy. They demonstrated that data collected during the study could accurately measure the replacement of muscle fibres with fat over time and even allowed the researchers to show that the onset of corticosteroid treatment slowed this process briefly. The conference finished with the award of prizes for the best poster presentations at the conference. Jenny Sharpe, a PhD student funded by the Muscular Dystrophy Campaign in Professor Michael Duchen’s laboratory at University College London was one of the winners – receiving a prize of £500 to be spent on attending a future scientific conference.

EXON SKIPPING The morning of the second day focused on the latest advances in exon skipping technology. The technology is currently in clinical trial for Duchenne muscular dystrophy and Professor Matthew Wood from Oxford University spoke about his research that aims to improve the efficiency of exon skipping technology by adding small pieces of protein (called peptides) to molecular patches. One talk highlighted the potential of exon skipping in spinal muscular atrophy and this was followed by Professor George Dickson from Royal Holloway University of London who spoke about his work aiming to develop exon skipping technology to develop molecular patches that can block the activity of a protein called myostatin, a protein naturally produced by the body that inhibits muscle growth. This approach is may be a useful way to “bulk up” muscles in people with a range of muscle conditions, helping to increase their muscle strength. As expected, molecular patches that reduce levels of myostatin increased the mass of treated muscle in both healthy and mdx mice (a mouse model of Duchenne muscular dystrophy). Tests of the technology at the same time as exon skipping for dystrophin showed that the technologies may have potential to be used together. This is encouraging and researchers are now trying to learn more about using combinations of molecular patches.

leading the way forward


Ask a Scientist

The Muscular Dystrophy Campaign research team is always available to answer any questions about research. Questions we don’t know the answer to, we refer to our network of scientists and clinicians working in the field.


In your articles about high throughput drug screens you often say that scientists are screening thousands of drugs to see what effects they have. This sounds very inefficient – why don’t scientists test fewer, better selected drugs? James Jarvis


Using high throughput screening of chemical compounds is a standard method used across the drug discovery industry. It is based on a specific high-throughput drug screening assay which is designed to enable researchers and companies to quickly and easily test (or screen) thousands (or even millions) of compounds to identify those which exhibit the specific activity which we are interested in. In our laboratory, where we aim to identify compounds that can increase levels of utrophin, we have developed a high-throughput drug screening assay where a light-producing gene has been inserted into the utrophin gene such that the amount of light produced by the cell tells us how much utrophin it is producing. Measuring the amount of light produced by the cell is far quicker, easier, and cheaper than measuring the amount of utrophin. Using our light-producing assay we can screen up to 96 compounds at one time. In some laboratories these tests are automated and are performed by robots – maximising the speed of screening by performing consecutive tests 24 hours each day. Whilst you are quite right that this can seem like an inefficient approach (often only a very small percentage of compounds that are screened have the desired properties), large-scale screening can enable researchers to identify compounds which we may not have predicted would have exhibited the specific activity. Where information is already available to suggest that particular compounds may be functional, we can preselect fewer compounds to screen. However, large scale screening lets us test these compounds

and more, so we can identify as many potential compounds as possible. Since we screen so many compounds, even a tiny percentage which exhibit the specific activity we are looking for (we call these “hits”) can provide us with lots of options to go on to investigate further using more traditional methods. Whilst these traditional methods are slower than the high throughput tests, they are necessary to provide us with more information about a compound and hopefully improve it so that it will be as effective as possible once it is inside the human body. Dr Rebecca Fairclough, University of Oxford

Q. A.

Do you fund research projects that use laboratory animals and will my donation be used to fund these projects? Terry Partridge The Muscular Dystrophy Campaign acknowledges some people have concerns about the use of animals in medical research. However, to find treatments and ultimately cures for muscular dystrophies and related neuromuscular conditions, we believe the use of animals in research, in strict accordance with the legal and regulatory guidelines, is necessary in order to derive full benefit from scientific advances. The Muscular Dystrophy Campaign funds research which utilises a wide variety of methods, some of which involve the use of animals. The Muscular Dystrophy Campaign will not fund animal research unless it is essential and there is no alternative. The UK has the strictest regulations in the world to control the use of animals in medical research. The Muscular Dystrophy Campaign is a member of the Association of Medical Research Charities (AMRC) and endorses its position on the use of animals in research.

The Muscular Dystrophy Campaign is committed to the three Rs approach: n



replace the use of animals with alternative techniques, or avoid the use of animals altogether reduce the number of animals used to a minimum, to obtain information from fewer animals or more information from the same number of animals refine the way experiments are carried out, to make sure animals suffer as little as possible. This includes better housing and improvements to procedures which minimise pain and suffering and/or improve animal welfare.

We do fund research projects that do not use animals, so if you would like the donations you make to the Muscular Dystrophy Campaign to be matched to projects that reflect your views about animal research, please get in touch with us on or phone 020 7803 4813. We also have family support programmes which rely on individual donations and family fundraising. Dr Marita Pohlschmidt, Director of Research at Muscular Dystrophy Campaign


My son has Becker muscular dystrophy. I’ve read that ataluren may be able to help people with Becker muscular dystrophy but don’t know if this is correct. If trials are successful could ataluren one day help people with Becker muscular dystrophy as well as people with Duchenne muscular dystrophy? Ben Kinder


Ataluren is a small molecule drug which is currently in a global phase 3 trial in boys with Duchenne muscular dystrophy caused by nonsense mutations. All genes have a stop codon at the end to tell a cell where the

gene finishes. Nonsense mutations are mutations which change a single base in the DNA to insert a stop codon in the middle of a gene – called a premature stop codon. This can stop the cell reading the rest of the gene and reduce or stop protein production. Ataluren enables read-through of the premature stop codon to produce a full-length dystrophin protein – effectively, ataluren can help cells to ignore the premature stop codons to read the entire gene all the way to the correct stop codon. Importantly, while ataluren is nonsense mutation dependent (it only has the potential to treat individuals with a nonsense mutation) it is what we call gene independent and it is therefore possible that ataluren may have the potential to treat some individuals with Becker muscular caused by nonsense mutations. Although the premature stop codon can prevent cells producing a fullsize, functional dystrophin protein, in some individuals natural exon skipping takes place. This can remove the exon containing the nonsense mutation and allow production of a shorter dystrophin protein which retains at least some functionality. In this way individuals may have a nonsense mutation in the dystrophin gene but may present clinically with Becker muscular dystrophy. The potential effectiveness of ataluren in these individuals is difficult to predict and relies on the efficiency of natural exon skipping. If there was 100% exon skipping, then ataluren would not work. However, that level of exon skipping is not expected and any mRNA molecules (the carbon copy of the DNA that carries the genetic information from the nucleus where genes are stored to the cytoplasm where proteins are made) that do not have an exon skipped could be amenable to ataluren therapy. This answer was compiled by the research team at the Muscular Dystrophy Campaign using information from PTC Therapeutics – the company developing ataluren. Alison Jones, PTC Therapeutics leading the way forward

Target MD and Target Research

Now more than ever, we rely on every penny of your donations to fund vital research and provide support and care for people with muscular dystrophy and related neuromuscular conditions. With this in mind, we‘re inviting you to subscribe to Target MD and Target Research – both to be delivered to you four times a year. That’s right! You will receive Target MD four times a year along with Target Research. And all for an annual subscription gift of just £18. This will help us cover our costs – even reduce them – while ensuring the same editorial quality you’d expect from every issue of Target MD and Target Research. And because they now only go to people like you who really want to read them, and they’re both now produced fully in-house, the Muscular Dystrophy Campaign can free up more funds to spend on further research, campaigning, support and equipment grants.

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Target MD Issue 2 of 4 2014 Registered Charity No. 205395 and Registered Scottish Charity No. SC039445

Target Research 2014 2 of 4  

In this issue of Target Research, we take a closer look at genetics and inheritance. Most of the conditions we cover are genetic, and this a...

Target Research 2014 2 of 4  

In this issue of Target Research, we take a closer look at genetics and inheritance. Most of the conditions we cover are genetic, and this a...