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A must read

Bringing clinical trials to the UK Target Research Issue 1 of 4 2013

Our investments to improve access to clinical trials for families in the UK

New clinical training fellowship awarded We interview Dr Saam Sedehizadeh of Nottingham University

Wading through the information jungle

thought provoking

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. Biobank – a place where researchers can securely store biological samples. 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. Cell - The structural and functional unit of all known living organisms. They are often called the building bricks of life. Humans have an estimated 100 trillion cells. Chromosome – cylindrical shaped bundles of DNA found in the cell nucleus. They consist of long, thread-like strands of DNA coiled up on themselves many times. We inherit 23 from our mother and 23 from our father. Cytoplasm – the area of a cell outside the nucleus where proteins are produced. 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. Drug screen – a way of testing many molecules (often several thousand) quickly, to test their potential to be used as a treatment for a disease. Dystrophin - The protein missing in people who have Duchenne muscular dystrophy and reduced in those who have Becker muscular dystrophy. The dystrophin protein normally sits in the membrane that surrounds muscle fibres like a skin, and protects the membrane from damage during muscle contraction. Without dystrophin the muscle fibre membranes become damaged and eventually the muscle fibres die. Exon – genes are divided into regions called exons and introns. Exons are the sections of DNA that code for the protein and 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. In-vitro fertilisation (IVF) – a process by which the egg is fertilised by sperm outside the womb. Magnetic resonance imaging (MRI) – a non-

invasive body imaging procedure that uses powerful magnets and radio waves to construct pictures of the internal structures of the body. 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. They can be used to mask errors in the genetic code, this is known as exon skipping and is in clinical trial for Duchenne muscular dystrophy. Certain types are also being investigated in the laboratory for their ability to completely switch off genes. Also called antisense oligonucleotides. Mutation – the alteration of a gene. 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 using it to find new genes and to diagnose genetic conditions more accurately. Non-sense mutation – a change in the DNA which causes a premature stop signal to occur in a gene. When this happens protein is either not produced at all or does not function properly. 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. 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. Placebo-controlled trial – a clinical trial where the effectiveness of a potential new drug is measured by comparing its effects to a placebo, or inactive drug. 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. RNA – Ribonucleic acid, a substance very similar to DNA. When a gene is ‘switched on’, RNA carbon copies of the gene’s code are made. The RNA moves outside the nucleus where they direct the manufacture of proteins. DNA can be thought of as a recipe book in the library that you can’t take out. RNA is a photocopy of a recipe that you can take home to cook something in your kitchen (making the protein). Zebrafish model – A tropical freshwater fish belonging to the minnow family. Researchers can create mutations in genes which can cause diseases similar to neuromuscular conditions in people. Importantly, zebrafish embryos are transparent, so we can easily observe their muscles developing.

The Muscular Dystrophy Campaign is the leading UK charity fighting musclewasting 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 research@ 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, 61 Southwark Street, London SE1 0HL 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 Target Research I’d like to welcome you to the first edition of Target Research this year, and to start the magazine by wishing all our readers a happy new year.


In this issue, we focus on the clinical trials infrastructure we are funding. Our main feature shows how our funding is helping to bring clinical trials to the UK, to make sure that people with neuromuscular conditions here don’t miss out on potential new treatments. We talk to the scientists and clinicians at Newcastle University who have recently started two clinical trials. We also interview Dr Saam Sedehizadeh – a clinician who has recently been awarded a Muscular Dystrophy Campaign-funded Clinical Training and Research Fellowship to carry out research into myotonic dystrophy at Nottingham University. And, as always, we have the latest research news stories from around the world including updates about exon skipping technology and the discovery of a new mutation linked to facioscapulohumeral muscular dystrophy type 2. I do hope you enjoy this edition of Target Research. If you have any feedback or there are any research questions you’d like us to answer in the next one, I’d love to hear from you.

Neil Bennett Editor, Target Research t: 020 7803 4813 e: tw: @NBennettMDC

Contents 4 Clinical trial infrastructure – bringing clinical trials to the UK 8 Research News – news from the UK and around the world 11 Wading through the information jungle – Dr Marita Pohlschmidt, the Director of Research 12 Introducing our new clinical training fellow – Dr Saam Sedehizadeh at Nottingham University 15 Ask a scientist – your questions answered by UK researchers

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

Investing in clinical trial readiness


As well as funding scientific research, the Muscular Dystrophy Campaign also invests money to bring clinical trials to the UK. This ensures that people with a muscular dystrophy or a related neuromuscular condition in the UK have access to new treatments as quickly as possible and helps companies and researchers organising clinical trials to recruit participants. In this article, we describe the projects we fund and highlight some of the clinical trials this funding has helped bring to the UK.


n the last ten years, the Muscular Dystrophy Campaign invested ÂŁ2.7M to help establish the muscle centres in London, Oxford and Newcastle. The set up has been so successful, that they have become model centres for some European countries. They provide clinics for thousands of people with muscle diseases each year, and the multidisciplinary teams in the centres ensure that patients have access to the best diagnostic and medical care available, including support from our local care advisors. There is still a need to support clinicians, and to get potential treatments to the

5 next step and into clinical trials. Building on the success of the muscle centres we are now funding projects which will ensure that people in the UK do not miss out on the opportunity to take part in clinical trials. These projects include patient registries and databases, clinical training and research fellowships, and clinical trials coordinators in the muscle centres in London and Newcastle. Clinical Trial Coordinators The running of a clinical trial imposes a massive administrative burden on the participating clinics, one which can often not be taken on without specialist help. The role of the trials coordinator therefore is to help with this administration and facilitate the setting up and running of the trials. Coordinators carry out a wide variety of duties related to the set up and running of clinical trials such as liaising with regulatory authorities, submission of vital documentation to appropriate bodies, such as ethics boards, identification of patients who may be suitable for the trial, helping with recruitment and information, planning often complex clinic visits, sorting out travel for patients to and from different appointments, data management, helping with monitoring visits and audits and essentially all aspects of trial design and execution. The coordinator is vital to the quality, safety and efficiency of a trial. The coordinator will guarantee that the research conducted is performed within the regulatory guidelines and also the specifications outlined in the trial protocol. They also ensure the trial complies with both departmental standard operating procedures on the conduct of research and external governance requirements. Without this role, it would be very difficult for muscle centres to take part in as many clinical trials. This is a key position which helps the muscle centres to participate fully in natural and international national history studies and clinical trials. Having this position at the muscle centres ensures that the families and individuals that the Muscular Dystrophy Campaign supports have early access to trials and potential new treatments.

Professor Katie Bushby, of Newcastle University said: “It was very far sighted of the Muscular Dystrophy Campaign to fund trial coordinators at the Muscle Centres in Newcastle and London. Running clinical trials is essential to move forward our understanding of muscular dystrophy and how to treat it, but the regulations that govern these processes are very stringent and complicated to navigate. Having dedicated trial coordinators means that we can dedicate experienced personnel to getting these processes followed properly and this has revolutionised the way we can approach trials and other studies in the UK. We have got a reputation now for excellent recruitment to studies and also very efficient running of trials and other studies. The trial coordinators are a crucial part of that, and we are delighted that the Muscular Dystrophy Campaign continues to be supportive of this crucial piece of the jigsaw for finding new therapies which are desperately needed.� Patient Registries and databases One of the challenges of organising clinical trials for rare diseases is finding enough participants. Trials for common conditions (like cancer) can often be carried out in a single hospital or country. However, to find enough participants with a rare disease, trial organisers must often run multinational or global studies; particularly in the later phases of clinical trials. Our funding of patient registries ensures that UK study centres can recruit trial participants quickly and efficiently. Registries contain information about individuals affected by a particular condition. When researchers or a pharmaceutical company are planning a clinical trial they can contact the curators of registries to find out how many people may meet the trial’s criteria. When recruitment to a trial starts, the trial organiser can approach the curators to find people who match and are interested in taking part. The registry curator can then contact these individuals to tell them about the trial. Whilst registries focus on the information needed to find patients eligible for clinical trials, they also have other benefits. The information they contain can help clinicians develop

standards of care and help people receive information about their condition. It should be noted that submitting your data to any of the registries does not mean that you are obliged to enrol in clinical trials; it just gives you the option of taking part. The Muscular Dystrophy Campaign provides funding support for the myotonic dystrophy registry and the FSH muscular dystrophy registry (which will start accepting registrations soon). For more information on registries for people with neuromuscular conditions look at our website at http://www. patient_registries. The Muscular Dystrophy Campaign also gives funding support to the UK National Neuromuscular Database. The database was initially developed as part of the Muscular Dystrophy Campaign-funded NorthStar project. It was set up by Professor Francesco Muntoni and Dr Adnan Manzur to collect natural history data from boys with Duchenne muscular dystrophy who are still walking. A similar database called SMArtNet which collects information on people with spinal muscular atrophy was later established. More recently these databases became the National Neuromuscular Database which has been expanded to include the conditions inclusion body myositis (IBM), the congenital muscular dystrophies and congenital myopathies. In the future it will also collect information about boys with Duchenne muscular dystrophy who use a wheelchair. The data held in the UK National Neuromuscular Database is collected from a large number of muscle clinics across the UK. This enables clinicians to compare the way people are treated in different clinics which helps to harmonise the care given by different hospitals. Natural history data also helps clinicians to put people diagnosed with a single condition into different subgroups. This improves understanding of how the disease progresses and means more detailed information can be given to families. A better understanding of disease progression can also help clinicians to design clinical trials in the future and help them to measure the effects of potential new drugs in clinical trials. leading the way forward

6 Limb girdle muscular dystrophy 2B/Miyoshi myopathy study An international team of researchers, led by Prof. Kate Bushby at Newcastle University has launched an international clinical study into limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. The study aims to identify methods which could be used to measure the effects of new potential drugs on disease progression and is being supported by the Muscular Dystrophy Campaignfunded clinical trial coordinator in Newcastle. Over the last few months, the first participants were enrolled in the “international clinical outcome study for dysferlinopathy”. The dysferlinopathies are a group of conditions that are caused by mutations in the gene that carries the genetic blueprint for the dysferlin protein. This leads to a deficiency in the dysferlin protein which can cause a spectrum of muscle diseases; the most common being limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Over the past decade, significant progress has been made in research into the dysferlinopathies, and new potential treatments for these conditions might soon be ready for

testing in clinical trials. However, to test the effectiveness of any new potential treatment researchers need to understand how the conditions progress and develop ways to measure the effects of trial drugs on disease progression. The study aims to better understand how symptoms change as the disease progresses and the tests which are most suited to measuring these changes. These features or tests are called “clinical outcome measures” and will be identified using a comprehensive set of medical, physiotherapy and MRI assessments. The study also aims to find biomarkers of the conditions. These are molecules in our body whose level changes in response to disease and which can be measured easily and in a non-invasive way. During the study, blood samples and skin biopsies will be collected from volunteer study participants to be stored in a “biobank”. These will be used by researchers in the future to identify biomarkers. Together, the identification of reliable biomarkers and clinical outcome measures will let researchers involved in future clinical trials monitor the effects of potential treatments in the best and most non-invasive way possible. Beyond Newcastle, the centres taking part in this study are located

in Germany, Spain, Italy, France, USA, Japan, and Australia. The researchers aim to recruit 150 people aged over ten years old who will be asked to visit a study centre six times over three years. The study is funded by the Jain Foundation in the USA and funds are available to cover travel costs for the study participants and a carer if needed. A study participant said: “I wanted to take part in this study as I, like many others, live in hope that one day a treatment will happen. If my contribution does not help me then I hope it may help others in the future. I was quite daunted at the thought of more tests but so far everyone has been great, a pleasure and a privilege to take part.” To find out more about the clinical study for dysferlinopathy, please see our clinical trials database here www. clinical_trials. Patients aged ten years or older, who have a genetically confirmed diagnosis of LGMD2B, Miyoshi myopathy or other “dysferlinopathy” and would like detailed information or to discuss participation, can contact the study team directly at contact@ or by phoning +44 (0)191 2418941.

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New clinical tria

7 ForDMD Trial The Muscular Dystrophy Campaignfunded clinical trials coordinator in Newcastle is also supporting the newly started ForDMD trial. Officially titled the “Duchenne Muscular Dystrophy: Double-blind Randomized Trial to Find Optimum Steroid Regimen”, researchers aim to recruit young boys (4-7 years old) with Duchenne muscular dystrophy who have not yet started taking steroids. The trial aims to identify the best way for doctors to give corticosteroids to boys with Duchenne muscular dystrophy. Treatment with corticosteroids is a part of the most recent standards of care, and the drugs have been given to boys with Duchenne muscular dystrophy for over 20 years. They are currently the only treatment that keeps boys walking for longer and and they may also help to prevent some heart problems. No proper clinical trial has ever investigated the best way to use steroids in boys with Duchenne muscular dystrophy over a long period of time. This means that different clinicians prescribe steroids differently – with the type and dose regime of steroid often varying between clinicans, hospitals and countries. In the UK there is a more or less 50:50 split

between boys on daily or intermittent regimes of prednisolone, but in the USA and Canada many doctors favour a different steroid, deflazacort. Which regime is used is more dependent on the clinicain prescribing it than on the results of any unbiased studies. A trial is needed to study this so that any bias in choice of steroid and any bias in the reporting of benefits and side effects can be taken out of the equation. The end result of this trial should be to find out which steroid and dose is most effective in boys with Duchenne muscular dystrophy and to examine the side effects caused by different treatments and how to minimise them. All boys in the trial will be given steroids, with one third receiving deflazacort and others taking prednisolone either every day, or intermittently (ten days on, ten days off ). The trial is being organised by Professor Kate Bushby at Newcastle University and Professor Robert Griggs at the University of Rochester in the USA. There are other trial sites located in Germany, the USA and Japan and ten locations in the UK. These include two hospitals in London, and one each of Leeds, Glasgow, Cardiff, Birmingham, Liverpool, Manchester, Newcastle and Oxford.

The researchers aim to recruit 300 boys aged between four and seven who have not taken steroids before. The participants will visit a trial site every six months for between three and five years; at each visit clinicans will perform a number of tests and measurements. These will include physical examination and checking vital signs (height, weight, waist circumference, blood pressure, pulse, and lung capacity). There will also be motor skills tests (jumping, hopping, time to stand from lying etc) and a six-minute walk test. Professor Francesco Muntoni, a clinician involved in the study said: “After many years of discussions regarding the best way to give corticosteroids to boys with DMD, this is the first study which will systematically compare efficacy and side effects of different regimens of steroids. This study will also provide additional information on how to best manage steroid-induced side effects in DMD, so it is a very important study that will have long lasting repercussions in the way steroids are prescribed worldwide”





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To find out more about the ForDMD trial, please see our clinical trials database at www.muscular-dystrophy. org/research/clinical_trials or go directly to the study website at www.for-dmd. org. On the website, you will also find the full list and contact details of the UK sites participating in the trial. People who are interested in participating in the trial and would like more detailed information or to discuss participation, can contact the study team directly at or by phoning +44 (0)191 2227623


als in Newcastle leading the way forward

8 next steps of the research. Building on the identification of good and bad perceptions, this included the design and testing of a training aid. The aid used a training technique called acceptance and commitment therapy to change the way people think of their neuromuscular disease. In a small scale test, the technique showed encouraging results but it would need to be properly tested in clinical trials before it could be offered to people with a muscular dystrophy or related neuromuscular condition in the clinic.



Quality of Life Study A group of scientists funded by the Muscular Dystrophy Campaign have completed a study analysing the role that different ways of thinking play in the quality of life of people with muscular dystrophy or a related neuromuscular condition.

In many chronic diseases, research has shown that individual differences in patients’ views of their illness may mean that even those with similar disease severity may have widely different quality of life. Perceptions of an illness are formed from information that patients receive from their doctor, family and friends and from the wider media. This may include views of the how the disease will progress over time, its cause and effects, and whether it can be controlled or cured. To investigate perceptions of neuromuscular conditions, the researchers sent people questionnaires which asked about the severity of their condition, their quality of life, and what they thought about their condition. The researchers received answers from 226 people and used a complicated statistical method called “cluster analysis” to analyse the information. This method highlights

groups (or clusters) of people who gave similar answers to the questions and showed that there were 3 separate groups. Two of these were of special interest because they had a different quality of life but the severity of their conditions was similar. Researchers thought the difference in quality of life between these groups could be caused by differences in how the individuals within the groups perceived their conditions.

People in the group with a higher quality of life tended to have more realistic views of their condition, and had accepted that it would be chronic (or long-lasting). People with a higher quality of life had also found ways to change their goals so they were still achievable, and to find ways to do the things they felt were most important to them. Researchers hope that by highlighting the perceptions that lead to the highest quality of life, they will be able to develop training aids which could help change how people think about their condition. Changing bad perceptions for good in this way could have the potential to improve quality of life in the absence of a treatment. At our national conference in November, Dr Chris Graham, one of the authors of the study described the

New FSH mutation found Approximately 95% of people diagnosed with FSH have FSH type 1. This condition is caused by a deletion (or contraction) in a part of chromosome 4 called the D4Z4 region. When this mutation is found near a piece of DNA called a permissive allele it can lead to abnormal production of a protein called DUX4 in the muscles. DUX4 controls how cells read many other genes, and so the production of the DUX4 protein alters the proteins produced in muscle cells and will eventually cause them to die. Around five percent of people with FSH are thought to have FSH type 2. People with FSH type 2 experience similar symptoms to people with FSH type 1 but have no deletion in the D4Z4 region of chromosome 4. Until now, people with FSH type 2 could not be given a precise genetic diagnosis. Now, an international team of researchers from the Netherlands, France and the USA has identified mutations that can cause FSH type 2. The researchers studied the DNA of 14 people with FSH type 2 and used a combination of techniques, including next generation sequencing, to look for mutations that might cause the disease. Mutations were identified in a gene called SMCHD1 in all 14 people. The gene carries the genetic blueprint for a protein called Structural Maintenance of Chromosomes Flexible Hinge containing 1, or SMCHD1 for short. This protein helps cells to stop genes being read when they are not required and one of the genes it helps to control is DUX4. Mutations in the SMCHD1 gene can therefore lead to the abnormal production of DUX4 which can lead to FSH muscular dystrophy.

9 The discovery of a mutation which causes FSH type 2 may help researchers to develop genetic tests for people with this condition. A precise genetic diagnosis is vital for helping families to understand the risk of passing the condition on to their children. It may also allow families to consider the option of using new technology when planning to have children. Knowing the genetic diagnosis allows clinicians to gather more precise information on how the disease might progress so affected families can plan for the future and gain access to appropriate care. In the longer term, this research will lead to a greater understanding of the biological mechanisms that are involved in FSH type 2. Identification of the SMCHD1 gene highlights a new mechanism by which FSH can be caused and may help researchers to develop therapies in the future. Pump implant may help people with Duchenne muscular dystrophy Duchenne muscular dystrophy is caused by a lack of dystrophin protein in the muscles. Dystrophin stabilises the muscle structure, and its absence leads to muscle damage and wasting. This muscle wasting also affects the heart muscle, weakening the muscle which pumps blood around the body and can eventually lead to heart failure. Now, surgeons in America have implanted a pump into a 29 year old man with Duchenne muscular dystrophy. They hope this will reduce the risk of heart failure and improve his quality of life. The pump, called a “left ventricular assist device”, is battery powered and helps the weakened heart muscle to pump blood around the body. It does not replace the heart. The pumps are often used in people waiting for heart transplants - to give doctors time to find a suitable donor heart. Whilst transplants are not feasible in people with Duchenne muscular dystrophy, the doctors who implanted the pump hope it will enable their patient enjoy a better quality of life for longer. They say it may even help him to survive until other treatments become available. With just a single case so far, this surgery is very experimental. Doctors will be monitoring how the heart and pump function; and how the pump affects the quality of life. Because

of the risks - the operation requires a general anaesthetic - involved in implanting a pump, the procedure will not be suitable for all boys or men with Duchenne muscular dystrophy. However, it is possible that this first case may help doctors and researchers to develop the technology to reduce the risk of heart failure in as many boys as possible. Enter the Variome The information contained in our DNA is stored as a long string of molecules called bases. The bases are represented by four letters (A, C, G, and T) and there are almost three billion letters in the human genome. These form over 23,000 genes which each hold the blueprint the body needs to produce a protein. The project to sequence the three billion letters in the human genome took thousands of scientists over 10 years and a billion pounds to complete. But knowing the sequences that make up a genome is one thing; making use of this information is another. New advances in sequencing DNA (reading the letters in the DNA code) mean it is becoming increasingly feasible is to sequence part or all of a person’s genome as a way to test for genetic diseases. However, it is sometimes difficult to tell whether differences between the published human genome and an individual’s sequences are harmless variations – different ways for the DNA blueprint to say the same thing – or mutations that might cause a genetic disease. The only way to tell for sure is to collect data from a large number of individuals and link certain mutations to certain diseases. This is precisely what the Human Variome Project aims to do. Researchers involved in the project aim to collect DNA sequences and information about symptoms and diseases from 40 countries worldwide which cover at least 30% of the world’s population. Researchers will then use this information to link mutations and diseases. By 2016 they hope to examine the role of 3,000 genes in disease; and by 2022, the researchers hope to have databases covering 8,000 genes – around one third of the total in humans.

will establish databases which will make the data available to clinicians and scientists around the world. This will help clinicians diagnose their patient’s faster and more precisely and will help scientists to design better experimental therapies and clinical trials. Ataluren conditional approval applied for In December PTC Therapeutics announced in a press release that they have applied for conditional approval of ataluren in the EU. Ataluren is an oral drug that has been developed to overcome a specific change in the DNA called a nonsense mutation. About 10-15% of boys with Duchenne muscular dystrophy have this type of mutation. Conditional approval is granted to drugs whose benefits are likely to outweigh their risks, but where additional information is needed to confirm this situation. Importantly, it allows treatments to be made available on the market whilst further studies are carried out. European regulators (the European Medicines Agency, or EMA) will now assess the application and decide whether to give approval to the drug. If conditional approval is granted, the company will be able to market the drug in the EU whilst a placebocontrolled phase 3 clinical trial is simultaneously carried out to confirm the safety and effectiveness of the drug. In the UK, the drug would still require assessment by the National Institute of Clinical Excellence and the NHS National Commissioning Board before a decision on whether to fund the potential treatment is made. It is not clear at the moment how long this process might take. The Muscular Dystrophy Campaign is looking at the UK funding and approval process for any potential treatment for Duchenne muscular dystrophy and representatives from the charity recently met with the Chair of NICE, Sir Michael Rawlins, to ensure that NICE is aware of the recent developments. We have also met representatives of the NHS Commissioning Board which will be responsible for funding any future treatments. 

Once the links between mutations and diseases have been made, the project leading the way forward


Hello from Target MD!

News in brief

Hello and happy new year to you all, from the team who puts together Target MD, the magazine that, together with Target Research, is the charity’s flagship publication. This is our first edition of the magazine for the year, and it focuses on travel and leisure. I hope that you will be inspired, encouraged, enthused and impressed by the stories that we feature in Target MD from many of our supporters.

Isis Pharmaceuticals SMNRx update Isis Pharmaceuticals has started a Phase 1b/2 clinical trial of a potential drug called Isis-SMNRx which may be able to treat spinal muscular atrophy. The condition is caused by a mutation in the SMN1 gene which carries the information to produce a protein called “survival motor neuron” which, as its name suggests, is needed for nerve cells to survive. The potential drug aims to take advantage of the fact that everybody has a copy of a related gene called SMN2. This gene mostly produces a shortened version of the SMN protein that does not work. Isis-SMNRx may be able to change the way the SMN2 genetic code is read, resulting in the production of a full-length, functional SMN protein.

In addition to introducing you to some more remarkable supporters, we bring you our latest campaigning successes and research updates, as well as news of our fundraising events from the last quarter of last year. And for those of you considering taking on some new challenges during 2013, on page 24 you’ll see a range of exciting running, cycling and challenge events to choose from. We’re keen to grow our subscriber base for Target MD and Target Research, so if you don’t already subscribe, please consider so after doing. Your support really helps us to continue our vital work. If you have any thoughts or comments about the magazine, or any ideas for future editions, do let me know. We do want to bring you the news and stories you want to read. I’d love to hear from you.

Ruth Martin Editor, Target MD t: 020 7803 4836 e: tw: @RuthWriter

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Researchers in the USA aim to recruit 24 children aged between two and 15 with spinal muscular atrophy and will evaluate the safety of Isis-SMNRx at different doses. This will let clinicians choose the best dose to test in future trials. EU Health Innovation Grant for Professor Francesco Muntoni Professor Francesco Muntoni at the Institute of Child Health in London and a team of researchers from Rome and Paris have been awarded an EU Health Innovation grant. Applications to this scheme are very complex, and the Muscular Dystrophy Campaign part-funded the company which helped the researchers to write the successful proposal. The team of researchers has now been awarded €5.5M (or £4.4M) and will work to further develop exon skipping technology. Working with Sarepta Therapeutics in the USA, the researchers will initially focus on the pre-clinical work required to develop a molecular patch for exon 53 of the dystrophin gene. If a molecular patch is successfully developed, the team will organise a small clinical trial (of 12 boys) to test the safety, tolerability and effectiveness of the molecular patch. Since molecular patches skip a specific exon in dystrophin, many different molecular patches will be needed if exon skipping technology is to reach as many boys as possible. This large investment from the EU for scientists to develop a new molecular patch is therefore encouraging news. However, it should be noted that like all other exon skipping technology this potential treatment would not cure boys with Duchenne muscular dystrophy, but might reduce their symptoms to those seen in boys with Becker muscular dystrophy. Dantrolene increases the efficiency of exon skipping in an animal model A group of scientists from California have used animal models to find a drug which might have the potential to increase the efficiency of exon skipping technology. The scientists screened 300 potential drugs and chose one called dantrolene to investigate further. This drug was chosen because it is licensed for use in humans, and has previously been tested for the ability to reduce muscle damage in boys with Duchenne muscular dystrophy with few side effects. Mdx mice – an animal model of Duchenne muscular dystrophy – given a molecular patch and dantrolone showed increased amounts of dystrophin in the muscles including the breathing muscles but not the heart; as compared to mice which were only given the molecular patch. Muscle function and the strength of the mice also increased. However, researchers do not fully understand how dantrolone is able to increase the efficiency of exon skipping in the animal model, and further work will be required before the potential drug could be tested in clinical trials.


Mitochondrial disease consultation Before Christmas, the Human Fertilisation and Embryology Authority finished a consultation to find out what the public thinks about new types of IVF being made available as treatments to let people with mitochondrial diseases have healthy children. These techniques were developed from Muscular Dystrophy Campaignfunded research led by Prof. Turnbull in Newcastle and the Muscular Dystrophy Campaign took part in the consultation. The techniques are controversial, because the child would inherit a small piece of DNA from a donor as well as the DNA from their parents. However, the DNA from the donor only affects how the mitochondria turn food into energy, and not the characteristics which makes us who we are. Some people believe that this small piece of DNA could lead to issues of identity (the child may feel uncomfortable about the donor DNA or may want to know who the donor was) or ethics (whether it would be acceptable for these IVF techniques to be moved into clinical trial and made available to people with mitochondrial disease). In our response we highlighted that the majority of our families felt that the donor DNA would cause no problems for the child, and that being able to have a healthy child is the most important thing. We also highlighted the importance of choice. Making these techniques available to the public would not force anybody to use them. However, it would give women with mitochondrial disease the possibility of choosing to have a child who is not affected. You can read our full response to the consultation at Authority_consultation.pdf New drug to be tested for use in the muscular dystrophies Prof Dominic Wells, and Dr Susan Brown, at the Royal Veterinary College in London recently received a grant from the Medical Research Council (MRC) as part of an innovative scheme that saw the MRC partnering with pharmaceutical company AstraZeneca. AstraZeneca made 22 of its chemical compounds available free-ofcharge to scientists, who were encouraged to apply for MRC funding to use them in medical research with the ultimate aim of benefiting patients. Prof Wells and Dr Brown will be testing a drug called AZD1236 for its ability to prevent scar tissue formation in muscular dystrophy.  The researchers will use the drug, originally developed to treat a type of lung disease known as chronic obstructive pulmonary disease, in two different mouse models of muscular dystrophy - Duchenne muscular dystrophy and limb girdle muscular dystrophy to see if they can slow progression of the disease. If successful, the study will provide the evidence needed to plan human trials of the drug to test whether it has a benefit for individuals with muscular dystrophy.

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Wading through the information jungle In this column I would like to take the opportunity to address something that I have wanted to raise for some time. There is a flood of information on the internet regarding the development of potential treatments for a number of neuromuscular conditions, especially the progress of clinical trials. This is in part due to more pharmaceutical companies becoming involved in this area and moving research forward. We need their commitment and investment, and it is heartening to see this growth. However, with it comes a flood of press releases, online articles, blogs and webinars. For affected families, the quantity of information can be both confusing and emotionally overwhelming. I recently talked to a mother of a boy with Duchenne muscular dystrophy – a tireless and fearless campaigner who had always seemed unshakeable. At the mention of a particular research project, she burst into tears. She told me that the waiting for a treatment which always seemed “just around the corner” was the heaviest weight to bear. Even I sometimes find it a struggle to keep abreast with the pace of new advances and to separate the truly significant developments from the noise. The Research team see it as our responsibility to translate and interpret for you how relevant and important the released information is. This is why we might not report on every single press release you will find online. But you can count on us to report on the ones that matter. Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign.

If you have any questions about this or any other research, please contact us: t: 020 7803 4812 e:

leading the way forward


Introducing our new clinical training fellow

13 The Muscular Dystrophy Campaign provides Clinical Training and Research Fellowships to encourage clinicians into an academic research career in the field of muscular dystrophy and related neuromusclur diseases. This year, Dr Saam Sedehizadeh at the University of Nottingham was awarded a fellowship. His research aims to bring us closer to clinical trial readiness for myotonic dystrophy type 1 and to identify potential drugs which may be able to treat myotonic dystrophy. Now we find out why Dr Sedehizadeh has chosen to train as a neuromuscular specialist and more details about his research project. Why did you choose to work in the field of neuromuscular disorders? The field of neuromuscular medicine encompasses a broad range of conditions. Seeing patients with many different conditions means that clinicians must develop a broad clinical knowledge and enjoy working in a multidisciplinary team. This attracted me to becoming a specialist in neurology and this, in my opinion, is the most interesting medical specialty. Working in the field of neuromuscular disorders will be a challenging job, but every day is different and this is very rewarding. What is your research project about and how does this fit WITH other research that is ongoing worldwide for myotonic dystrophy? Myotonic dystrophy is the most common form of muscular dystrophy in adults. Type 1 myotonic dystrophy is caused by a mutation called a “triplet repeat expansion” which is an enlarged repetition of a short segment of DNA in a gene called DMPK. When cells make proteins, the instructions held in the genes have to be sent from the cell nucleus (where DNA is kept) to the cytoplasm, where the protein is made. The cell uses a molecule called RNA - a carbon copy of DNA – as a messenger. When the cell copies the DMPK gene into RNA, the “triplet repeat expansion” is also copied into the RNA. This RNA gets trapped inside the nucleus where it forms

clumps. These clumps often contain proteins. Proteins can get caught up in these clumps which can stop them working properly, and lead to muscle cell damage. There have been several major advances in working out the link between the expanded RNA and muscle cell damage; and this has really improved the prospects of finding treatment options for people with myotonic dystrophy in the foreseeable future. These advances have also led to the development of various approaches to identify potential drugs that might be able to destroy the expanded RNA to disrupt the clumps. However, before these potential treatments could be tested in clinical trials, it is important to improve our understanding of the disease progression and to develop ways to measure the effectiveness of any new treatment. The two main objectives of the study are therefore to identify biomarkers that could be used to monitor disease progression in people with myotonic dystrophy and to try to find drugs that may potentially be useful for treating myotonic dystrophy type 1. Biomarkers are molecules in our bodies whose levels vary in response to disease and which can be easily measured in a non-invasive way. One challenge in identifying biomarkers is to link the level of molecules in the muscle or blood with disease symptoms and severity. To address this challenge, we will perform medical assessments and take muscle biopsies and blood samples from people with myotonic dystrophy and healthy individuals once a year, for 3 years. The annual medical assessment will comprise clinical measures of muscle strength and mass, and walking speed. Taken over three consecutive years, these assessments will enable us to link symptoms and signs (e.g weakness) with the levels of molecules (or biomarkers) in the muscle or blood. The biomarkers we identify could be used in future clinical trials to test the effectiveness of the treatment being tested. We are also going to screen a library of 5,000 drug-like molecules for their potential to treat myotonic dystrophy type 1. Using a drug screen – a method for testing the effects of many

different molecules – developed by Professor David Brook’s laboratory in Nottingham, we will test whether any of the 5,000 drug-like molecules are able to reduce the number of clumps of expanded RNA in cells and whether help the trapped RNA out of the nucleus. Any of the molecules that show potential as a treatment will be further tested in a Zebrafish model – an animal model of myotonic dystrophy. This will let us confirm their ability to disrupt the clumps of expanded RNA. How will your research help us to come closer to a treatment for myotonic dystrophy? This research could find drugs that might have the potential to be developed to treat people with myotonic dystrophy type 1. In addition, the study also aims to identify “outcome measures” and biomarkers. Outcome measures are symptoms of disease that can be used to monitor disease progression and the effectiveness of any new potential treatment. This work could bring us a step closer to being ready to start clinical trials of potential new treatments for myotonic dystrophy What do you think your average day will look like once you have started the fellowship, with juggling both research and clinical work? The Muscular Dystrophy Campaign fellowship gives me the opportunity to spend time in both the laboratory and clinic. My research will be divided between Professor David Brook’s laboratory and the David Greenfield human physiology laboratories. In Professor Brooks laboratory I will carry out the screen of potential new drugs for myotonic dystrophy. In the physiological laboratories I will carry out the clinical assessments of study participants which will let us identify biomarkers. I plan to spend around one day a week recruiting and assessing at least 40 myotonic dystrophy patients and unaffected volunteers both at the start of the study and during the follow-up phases. Once every two weeks, I will attend the muscle clinic at Queen’s Medical leading the way forward

14 Centre, Nottingham. This will let me continue my clinical training and help me to learn more about treating and diagnosing people with a muscular dystrophy or related neuromuscular condition. Tell us more about the muscle clinic where you work As a Specialist Registrar in Neurology I will work as part of a team in Nottingham. The head of the specialist muscle clinic is Dr Maddison, and his clinic at the Queen’s Medical Centre, Nottingham cares for patients with a wide range of neuromuscular disorders and other muscle problems. The clinic works as a multidisciplinary team, which includes physiotherapists, speech and language therapists, rehabilitation services and other medical specialists. The clinic is part of the UK neuromuscular network, which brings together neuromuscular specialists from around the country, and gives the clinic close links with the muscle centres in Oxford and Newcastle which can provide specialist diagnostic support. The Nottingham clinic has a significant research focus and recruits participants to numerous research projects, both locally and nationally. I will also be able to recruit participants from the Royal Derby Hospital where Dr Margaret Phillips runs a rehabilitation clinic which treats people with neuromuscular conditions. How will the funding from the Muscular Dystrophy Campaign help your career? The Muscular Dystrophy Campaign Clinical Training and Research Fellowship will allow me to pursue a research project that I am enthusiastic about and will build on preliminary work undertaken in Professor Brook’s laboratory. Ultimately I hope to continue postdoctoral research through intermediate clinical fellowships/lectureships as a research clinician. This will let me continue research with the aim of developing treatments in the field of neuromuscular diseases. This fellowship is a crucial step along the path towards reaching my goal of becoming a research clinician. The fellowship will provide me with

training in both research and clinical settings. In the laboratory, I will use cutting edge laboratory techniques and develop research-based skills alongside working in the muscle clinic where I will learn more about diagnosing and treating people with neuromuscular diseases. What do you think are the biggest research advances made in the field of neuromuscular diseases in the last year? Significant advances in understanding the genes and proteins which cause muscular dystrophies have led to various approaches which specifically target disease mechanisms and have helped scientists to develop drug screening assays. In particular the development of exon skipping technology which uses molecular patches to mask a part of a gene where there is a mistake has shown promising results in early clinical trials in Duchenne muscular dystrophy patients. In addition, pioneering research at Newcastle University has developed an IVF technique that has the potential to stop mitochondrial myopathy being passed from mother to child and this is currently being addressed in the Human Fertilisation and Embryology authority public consultation. Who is your scientific hero? Having completed my undergraduate training at the University of Leicester, I have great admiration for Professor Sir Alec Jeffreys who invented DNA fingerprinting at the university in 1984. Researchers were attempting to identify the gene carrying the information for a protein called myoglobin – which carries the oxygen in muscle, During these experiments, the team identified a repetitive piece of DNA which was similar in different members of a family. This repetitive piece of DNA was used in subsequent studies and eventually led to the discovery of DNA fingerprints which are unique to an individual. This discovery has revolutionised forensic science, and paternity testing. What are your other interests? I enjoy watching and playing racquet sports including tennis and badminton. My other hobby is landscape photography. All my remaining time is spent entertaining my young daughter!

What is a clinical training and research fellowship Clinical Training and Research Fellowships are available to encourage clinicians into an academic research career in the field of muscular dystrophy and related neuromuscular diseases. They are open to medical graduates, usually during speciality training, and aim to provide an opportunity for training in clinical and/ or laboratory research techniques in a project that demonstrates clear relevance to the aims of the Muscular Dystrophy Campaign. Clinical Fellowships are ideally placed to promote our strategic aim of funding translational research. This is the “bench-to-bedside” transfer of promising technology into a patient benefit and can be a particularly challenging process. The clinical fellows have one foot in the laboratory and one foot in the clinic giving them the unique opportunity of aiding this process and helping with the development of treatments. We hope that the clinical fellows will take the skills and knowledge they acquire during this training to benefit patients and families at clinics where that expertise might otherwise have been lacking.


Q. Many clinical trials in your

database seem to use Magnetic Resonance Spectroscopy. What are the differences between Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging? James Russell

A. Both magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) use similar technology. However, the techniques give us different information - MRI is used to produce pictures of the inside of the body; MRS can tell us about the levels of different molecules in the body’s tissues.

Imagine taking a photograph in the dark: the flash on the camera fires light at the subject. Different colours reflect light differently and the camera is able to detect these differences using light-sensitive film (or a computer chip) to make a picture of the subject. MRI is very similar, but takes pictures of the inside of our bodies using radiowaves to build the picture instead of light. To create the picture, the MRI scanner sends radiowaves (the flash, in the photograph) into the body which the different tissues in the body absorb and then release (the reflection of the light in the photograph). The MRI scanner then uses a receiver coil – which is just a fancy aerial – to detect these radiowaves, just like the film in your camera detects light. At present, MRS is mainly used in research and in clinical trials. In some ways, MRS could be thought of as taking a picture with a different filter on the camera lens, so rather than a producing a picture of the structure of the muscles, we can detect the chemical substances inside them. We can look at the chemical substances that power our legs, arms and hearts. We can measure the amount of the

chemicals present and monitor how they are altered in muscle diseases and how they change with disease progression. We can then measure accurately whether they could be returned to normal by new potential treatments in clinical trials. Dr Kieren Hollingsworth Newcastle University

Q. I’ve just been given the results

of a genetic test for FSH muscular dystrophy. The results are very detailed, so please could you explain how the test works? Judith Rogers

A. Inside our cells, the DNA is held

together and organised into structures called chromosomes (46 in humans grouped into 23 pairs). The genetic test for Facioscapulohumeral muscular dystrophy looks for a mutation in a part of chromosome 4 called the D4Z4 region. This mutation, which causes approximately 95% of cases of FSH, results in loss of a part of the D4Z4 region (this type of mutation is termed a deletion). This region of DNA is composed of a repeating piece of DNA, with each unit in the repeat made of a piece of DNA which is 3.3kb long. A “kb” is simply a measure of the length of a piece of DNA – just like car journeys are measured in miles, DNA length is measured in kb.

the genetic test identifies pieces of DNA from this part of chromosome 4 which are shorter than 35kb. Clinicians can use the presence of the shorter piece of DNA to diagnose people with FSH. Not everyone with such a short piece of DNA will have FSH. For the mutation to cause disease, the shortened repeat must be in close proximity to a specific DNA sequence (called a permissive allele). Not everybody has this particular sequence, so not everybody with the shortened fragment will have FSH. However, testing for this “permissive allele” is not currently carried out, so diagnosis also relies on the symptoms of the condition. It must also be noted, that approximately 5% of people with FSH do not have a mutation in the D4Z4 regions and researchers are currently working to identify mutations that cause the disease in these individuals. Some genetic test results may also mention chromosome 10. This information is only collected to make sure that the test has worked as it should. Professor Jane Hewitt University of Nottingham

Healthy individuals typically have at least 10 copies of the repeating unit, meaning that in total the region is at least 35kb long. People with FSH typically have less than 10 copies, so

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 this article we posed some of the questions we have received recently to top researchers for further expert opinions.

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Your questions answered A MUST READ

Exercise for people with neuromuscular conditions An update into the exercise studies we funded from the scientists who led the research teams.

HFEA launches mitochondrial disease consultation Make your voice heard Also inside… read about all the latest research and clinical trial news from the UK and around the world

Target Research 2013 (1 of 4)  

The main feature in Target Research is about the clinical trials infrastructure we fund to make sure that people with neuromuscular conditio...