Target Research 2014 (1 of 4)

Target Research Issue 1 of 4 2014

New Clinical Training and Research Fellowship awarded We interview Dr Lizzie Harris at Newcastle University

Paving the way to treatments Our research strategy 2013-2018

Would you like to join our ‘Talk Research’ group?

Help to shape our research communications

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

2

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.

About us

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.

The Muscular Dystrophy Campaign is the leading UK charity fighting muscle-wasting conditions.

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.

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 cause 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.

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.

www.muscular-dystrophy.org/research

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.

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 very similar protein 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.

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@muscular-dystrophy.org 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: info@muscular-dystrophy.org w: www.muscular-dystrophy.org 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

Cover photo: dra_schwartzistock

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.

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.

3

Welcome

I’d like to welcome you to the first edition of Target Research of 2014, and to start the magazine by wishing all our readers a happy new year!

In this issue, we focus on our new research strategy. The strategy was produced in consultation with leading scientists and clinicians, as well as our families, and it defines how the charity will fund research and what types of research we will fund over the next five years.

We also interview Dr Lizzie Harris – a clinician who has recently been awarded a Muscular Dystrophy Campaign-funded Clinical Training and Research Fellowship to carry out research into limb girdle muscular dystrophy at Newcastle University.

As always, we also have the latest research news stories from around the world including updates on clinical trials. I do hope you enjoy this edition of Target Research. If you have any research questions you’d like us to answer in the next one, I’d love to hear from you.

Neil Bennett Editor t: 020 7803 4813 e: research@muscular-dystrophy.org tw: @ResearchMDC

Contents 4

Our new research strategy What research will we fund in the next five years?

8

Research news The latest research and clinical trial updates from around the world

11 Talk research is recruiting

Help us to improve how we communicate research 12 Introducing our new clinical fellow

We interview Dr Lizzie Harris 15 Ask a Scientist

Your questions answered by UK researchers 15 My personal challenge

Dr Marita Pohlschmidt, Director of Research Follow us on: www.facebook.com/musculardystrophycampaign Follow us on: www.twitter.com/TargetMD leading the way forward

4

www.muscular-dystrophy.org/research

5

Paving the way to treatments Research Strategy 2013-2018 The Muscular Dystrophy Campaign is the leading UK charity providing support for more than 60 different muscular dystrophies and related neuromuscular conditions affecting 70,000 people.

The charity was founded in 1959 as a medical research charity and funds internationally competitive research with a strong UK focus.

Since our foundation, our investment in science has led to the identification of many genetic defects that can cause a neuromuscular condition. This in turn has led to improved diagnosis and care and has given scientists a better understanding of muscle function and the underlying biological processes leading to muscular dystrophy or one of the related neuromuscular conditions. Research funded by the charity has spearheaded some groundbreaking therapeutic developments that are now being tested in clinical trials. This has also been the catalyst leading to further major funding from institutions such as the MRC and the Wellcome Trust of which an example is the establishment of the Wellcome Trust Centre for Mitochondrial Disease at Newcastle University.

However, no effective treatment or cure is currently available for the majority of the conditions the charity provides support for and their development remains the ultimate goal at the very heart of the research the Muscular Dystrophy Campaign funds.

The muscular dystrophies and related neuromuscular conditions are regarded as rare or, in some cases ultra-rare, conditions with as few as 10 known individuals affected by them in the UK. This is the reason why they are often overlooked by government and other funding agencies, the academic community and the pharmaceutical industry. In recent years this has started to change with the establishment of international initiatives and networks that aim to bring together globally available resources and to implement the infrastructure necessary for promoting clinical trial-readiness.

In light of these developments and as a requirement of our AMRC membership, the charity has reassessed the aims set out in the research strategy defined in 2007.

The challenges are numerous. We fund research into many conditions all of which are at different stages in the search to finding treatments. Identifying the research areas that promise to make the greatest scientific advancements but also have the most relevance for our families is crucial to maximise the impact of the limited funds that are available. Owing to the rarity of the conditions it is also fundamental that our activities are aligned with international developments to ensure that the charity does not fund research in the UK that is unnecessarily duplicating research ongoing elsewhere in the world. We also want to ensure that the UK is well-prepared to participate in international clinical trials so that our families have early access to what could be potentially life-saving treatments.

It will be essential to build on the successes of the last decade and to finally bring those treatments that are so desperately needed to the market. The research strategy is summarised on the next two pages, but if you would like a copy of the full document please do get in touch.

The research strategy describes eight different strategic topics in which investment is required.

These are:

GOAL 1 To develop potential therapeutic approaches

GOAL 2 To promote clinical trial readiness

GOAL 3 To support clinical trials and pilot studies

GOAL 4 To understand the cause of neuromuscular conditions

GOAL 5 To build clinical and scientific capacity

GOAL 6 To improve quality of life

GOAL 7 To foster sharing of knowledge and networking

GOAL 8 To build partnerships leading the way forward

Our strategic

goals at a glance GOAL 1

To develop potential therapeutic approaches We will fund research to optimise exon skipping and explore its potential for other conditions, to develop technology that aims to repair the genetic defect, to identify drugs that target underlying biological processes and to further the understanding of stem cell biology.

GOAL 2 To promote clinical trial readiness We will invest in the national clinical infrastructure by providing support for patient registries, national history databases and clinical trial co-ordinators.

GOAL 3 To support clinical trials and pilot studies We will fund small pilot studies based on the rationale of repurposing drugs for the benefit of people with neuromuscular conditions and plan to play a role in bringing experts together to conduct the first stages of clinical trials to test sophisticated new therapeutic approaches.

GOAL 4 To understand the cause of neuromuscular conditions A significant proportion of people with neuromuscular conditions have not received a diagnosis and the charity will continue to fund research as part of larger initiatives to find new disease genes and understand their role in causing the condition.

GOAL 5 To build clinical and scientific capacity The charity will encourage young scientists and clinicians to take up a career in neuromuscular conditions to ensure that future generations have the same excellent quality they have today by providing PhD studentships and Clinical Training and Research Fellowships.

GOAL 7 To foster sharing of knowledge and networking

GOAL 6 To improve quality of life We will fund research into improving clinical care, finding ways for better managing the different conditions and understanding those factors that have a positive impact on the quality of life for affected individuals as well as their families.

Illustration: istock

In the coming years we will encourage the establishment of a national and international infrastructure that allows researchers from different disciplines to efficiently communicate and collaborate to ensure the speedy translation of promising technology into a clinical benefit.

GOAL 8 To build partnerships We are keen to represent the patients’ views in European and international projects and to work together with other charities and funding institutions such as the Medical Research Council, Chief Scientific Office Scotland and the Wellcome Trust whenever a suitable opportunity arises.

News 8

Research

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

Research with zebrafish takes us one step closer to stem cell transplantation A group of researchers in the USA has used a screen in zebrafish cells to identify factors that promote muscle formation from stem cells that could be used to develop future stem cell transplant. The zebrafish cells were genetically modified so that the researchers could trace their development into muscle tissue. By treating the cells with a number of different compounds, factors that promote muscle cell formation could be detected, and after testing 2,400 compounds, six were identified that drove the development of stem cells to muscle cells.

Two major obstacles to stem cell therapies are getting sufficient cells to transplant and controlling their development into muscle cells. Finding factors that can increase stem cell numbers and push them towards becoming muscle cells as opposed to other types of cell is an important step towards overcoming these challenges.

The researchers found that one of the six identified compounds, called forskolin, increases the division of muscle stem cells – called satellite cells – grown in the laboratory. The cells increased in number, retained their important stem cell characteristics and were successfully transplanted into mice.

A cocktail of three identified factors, including forskolin, was tested on human iPS cells in the laboratory. iPS cells are similar to embryonic stem cells but are made in the laboratory by genetically re-programming adult cells; researchers hope this could be a useful source of stem cells. When treated with the cocktail, iPS cells developed into satellite cells and muscle cells, a far more efficient way of generating satellite cells in the laboratory than traditional methods, which are lengthy and often require genetic manipulation. When the satellite cells were transplanted into mice with injured limb muscles, the transplanted cells showed typical properties of satellite cells: repairing muscle damage and re-populating the stem cell pool, which acts as a store of dormant satellite cells that become activated when muscle tissue is damaged.

This research is an important step towards the development of stem cell therapy for people with muscular dystrophy and related neuromuscular conditions. It demonstrates a simple method of generating large numbers of satellite cells in the laboratory. Satellite cells are the key stem cells in adult muscle, making them an attractive choice for transplantation in people with neuromuscular conditions. A big challenge is producing enough cells for transplantation, but this new method could help researchers overcome this hurdle. However, the technique is still in the early stages of development, being tested in animals, and more research is needed before it can be tried in humans.

Particularly, it is crucial to ensure the behaviour of the transplanted stem cells can be controlled, otherwise there is a risk they could become cancerous in the body. www.muscular-dystrophy.org/research

Modifier gene found in FSH As reported in Target Research last year, a team of researchers identified mutations in a gene called SMCHD1 which can cause FSH type 2 – a rare form of the condition affecting around 5% of people with FSH. Researchers have now discovered that the same gene may affect the severity of FSH type 1 – the most common form of the condition caused by a deletion in the DNA on chromosome 4. This deletion allows muscle cells to produce a protein called DUX4 which is not normally made in adult muscle cells. DUX4 is a transcription factor – a molecular switch – which can turn other genes on and off and this eventually leads to the death of muscle cells.

Although scientists believe that the size of the deletion in chromosome 4 is linked to the severity of the condition, variation in disease severity is seen in people with similar deletions. This suggests other factors may play a role and researchers have shown that SMCHD1 can play a role as a modifier gene.

Modifier genes are those which may not cause a condition but can affect the severity of the symptoms. Mutations in SMCHD1 are also thought to allow DUX4 protein to be produced, and since both mutations affect the same biological pathway, it is possible their effects may be additive, something researchers are now investigating further.

9

The search for biomarkers for spinal muscular atrophy An international team of researchers including Muscular Dystrophy Campaign-funded Prof Thomas Gillingwater and his team have published a study which has identified two potential biomarkers for spinal muscular atrophy (SMA).

The study used a cutting edge technique called proteomics to study a vast number of proteins at the same time. In this technique, muscles from a mouse model of SMA or healthy mice were frozen and then broken down into their component proteins using enzymes. Another cutting edge technique called mass spectrometry was then used to measure the make-up of each protein to allow researchers to identify them. This gave researchers a list of the proteins being produced in healthy muscle and muscle from a mouse model of SMA and by comparing the two they were able to find proteins whose levels were changed by the condition.

The researchers identified 23 proteins, the levels of which were increased or decreased during disease progression in the mouse model and believe these may have the potential to be used as biomarkers. To confirm the results, researchers tested the same proteins in different animal models of SMA. This highlighted two proteins, the levels of which correlated with the condition called calreticulin and mortalin.

An initial examination of the levels of these proteins in samples from people with SMA showed that the levels of the proteins does vary with disease stage but further work will be required to fully validate these proteins as biomarkers for the condition.

For more information about biomarkers and how they are validated, please look at Target Research Issue 4 of 4 2013. You can also read a full interview with Prof Gillingwater in Target MD. Do pop over to p16 of our lifestyle magazine to meet the man behind this research.

Summit announces plans for alliance and new trials In recent press releases, Summit Corporation Plc has announced a new clinical trial for Duchenne muscular dystrophy and a new strategic alliance.

The company has received ethical approval to start a phase 1b trial of SMT-C1100 in the UK. Last year the company completed a phase 1a study which showed that the potential drug appeared safe and well-tolerated and that is was distributed around the body in the bloodstream. In the new trial researchers will test the safety of different doses of SMT C1100 and will monitor how well they are tolerated by boys with Duchenne muscular dystrophy and how much of the molecule reaches the bloodstream.

This information will be crucial for planning future clinical trials which will test whether the potential drug can increase levels of utrophin in people with Duchenne and Becker muscular dystrophy and whether this is beneficial for these individuals.

The phase 1b trial will recruit 12 boys aged between five and 11 and will take place at four hospitals around the UK. The trial will start shortly and we will bring you more details as they become available.

Summit has also announced the formation of a strategic alliance with Oxford University to further research into the up-regulation of utrophin. The company already has a potential drug (called SMT C1100) in clinical trial and the new partnership will see them working closely with Professor Dame Kay Davies and Dr Angela Russell at Oxford University to identify new compounds that can up-regulate utrophin and to develop them for testing in clinical trials.

The Muscular Dystrophy Campaign has funded research for many years which aims to develop up-regulation of utrophin as a therapeutic approach to treat Duchenne and Becker muscular dystrophy. We recently announced further funding (with the Duchenne Forum) into this approach, with research projects in the laboratories of Prof Davies and Dr Russell. The new agreement between Oxford University and Summit will see this work move forward more quickly as Summit will give support and resources to the university and will sponsor further research projects in the laboratory. In return, the company will be given the rights to take any new potential drugs identified in the research projects into clinical trial.

This partnership is a good example of how universities and companies working in partnership can benefit people affected by a condition. Not only will the agreement see more new potential drugs identified, but it will give them a clear path towards clinical trial. It also shows how partnerships can increase the effectiveness of funding – in this case the effectiveness of our initial investment (with the Duchenne Forum) into these laboratories will be greatly increased by the additional resources provided by Summit and the work will move forward more rapidly and on a larger scale.

Clinical Research and Training Fellowship in Scotland for Duchenne muscular dystrophy In November, the Scottish Public Health Minister Michael Mathieson announced that the Chief Scientist Office would form a partnership with the Muscular Dystrophy Campaign and Action Duchenne to fund, together, the work of a young medic training to specialise in Duchenne muscular dystrophy, and a call for applications for a Clinical Training and Research Fellowship in Scotland will be issued shortly.

Clinical Training and Research Fellowships can encourage clinicians into an academic research career (see page 14 for more information). They are open to medical graduates, usually during speciality training, and in this case, the Fellowship aims to provide an opportunity for training in clinical and/or laboratory research techniques related to Duchenne muscular dystrophy.

The Fellowships are ideally placed to promote translational research. This is the ‘bench-to-bedside’ transfer of promising technology from the laboratory into a patient benefit and can be a particularly challenging process. Clinical fellows, with one foot in the laboratory and one foot in the clinic, have a unique opportunity to aid this process and help the development of treatments. leading the way forward

10

Now Recruiting: A new study investigating the importance of psychological factors over time.

Dr Christopher Graham is a Trainee Clinical Psychologist at the University of Edinburgh and NHS Lothian. Last year he completed a PhD funded by the Muscular Dystrophy Campaign and now he hopes to extend his work.

Over the past few years research has set about understanding why there are many people with muscular dystrophy who experience a very high quality of life - even with symptoms at their most severe. Past studies, which used questionnaires and interviews, and undertook a small trial of a self-help book have suggested that people’s beliefs about their condition are important in explaining good adjustment to life with a neuromuscular condition; those with more realistic beliefs about how long muscle disease might last and a less negative emotional response to muscle disease, appear to do best, whilst people who can focus their attention on activities that they find meaningful, such as keeping up with friends, hobbies, travel or employment, also tend to do better.

However, some important questions still remain, and perhaps the most important of these is: what is it that protects people’s quality of life from being affected by a worsening of muscle disease symptoms over time?

Dr Graham has now started a new study and you can take part! This study could give the clearest answers to the questions so far and could help researchers to design better ways to support people as they adjust to living with neuromuscular conditions.

It will appear shortly on our website and involves completing two short questionnaires, three months apart.

These shouldn’t take much more than 30 minutes to complete, and as many responses as possible are needed. www.muscular-dystrophy.org/research

Research news

in brief FDA say an application to licence eteplirsen would be premature Sarepta Therapeutics announced in November that the Food and Drug Administration (FDA, the American drug regulator) in the USA considered the company’s plans to file an application for eteplirsen – a molecular patch for exon 51 of the dystrophin gene – to be licensed as premature.

The FDA is basing their decision partly on the results of the large phase 3 clinical trial carried out by GlaxoSmithKline and Prosensa that showed that drisapersen – a drug similar to eteplirsen – failed to show that boys who received the drug could walk further than those that received placebo (an inactive form of the potential drug). They also state that there are new findings regarding the natural progression of Duchenne muscular dystrophy, which suggests that the stabilisation observed during Sarepta’s phase 2b extension trial might not be caused by the drug but could be due to the natural course of the condition. The trial involved only a small number of boys and a larger study will be needed to demonstrate that eteplirsen is an effective treatment. The FDA also expressed doubts that dystrophin can be used as a biomarker in clinical trials. Biomarkers are biological substances found in blood, urine or other parts of the body that can be used as an indicator in clinical trials to see how well the body responds to a potential treatment. In the FDA’s opinion, there is not sufficient knowledge about the levels of dystrophin protein that are needed in the muscle to assume that its levels can show whether a treatment will be effective. Sarepta Therapeutics is committed to continuing with a phase 3 trial which they plan to start early next year. The trial will involve about 120 boys. We will keep you informed as we receive more details.

National Conference Report Our National Conference was held in Nottingham in October – a chance for us to meet our supporters and families and to try to answer any research questions you have.

This year we were joined by many of our young scientists and Clinical Training and Research Fellows who brought posters describing the research projects they are working on. This interaction between researchers and families is important for both groups. On one hand our supporters can ask questions directly of scientists to learn more about the research we are funding; on the other hand it gives our researchers an opportunity to meet individuals affected by neuromuscular conditions and to learn more about the issues which they think are most important. As part of the research poster session, two science communication prizes were awarded for the best presentations in lay language. Dr Gillian Hunter from Prof Gillingwater’s group in Edinburgh and Leanne Liscomb from Prof Steve Winder’s group in Sheffield were chosen as the winners by the judging panel.

11

Would you like to join our Talk Research group?

Talk Research is a group of supporters keen to have a say in how we communicate research – giving us feedback and suggestions about the news stories and magazines that we publish. We’re looking for new recruits!

Over the last few years the Muscular Dystrophy Campaign has been putting greater emphasis on involving families and supporters in the way we allocate funds for research and communicate new advances from all around the world. However, we are keen to have your input in how we this present information and whether we use the right language that is easy to understand.

As well as the Lay Research Panel which examines applications – written in lay language – for research grants, we established a group we call “Talk Research”. This is a network of supporters who are keen to have a say in how we communicate research – giving us feedback on the news stories we publish on the website and the topics we cover in Target Research.

The group mainly communicates by email but meets from time to time at the Muscular Dystrophy Campaign office in London. In these informal meetings, examples of our articles are scrutinised. Feedback we receive is invaluable and we also have sessions to gather ideas on how to improve our research communications.

If you are unable to travel to the meetings you can join us by phone.

We’re looking for new recruits for the “Talk Research” group. If you are interested in joining the group, please get in touch with Neil at research@muscular-dystrophy. org or on 020 7803 4813. We plan to have a meeting in summer 2014 and will send out details nearer to the time. You can be as involved as you’d like to be, and it’s a great way to “dip your toes” into research!

Hello from Target MD On behalf of the team at Target MD, I’d like to wish you an excellent, successful and rewarding year ahead.

Our first edition of Target MD for 2014 has a distinctly Scottish focus and we introduce you to just some of the outstanding people doing amazing work in Scotland for the charity. There’s also news of campaigns and Trailblazer activities in Scotland, including our new Link Up project that brings young and older Trailblazers together in an exclusively Scottish mentoring project.

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. The first-ever Powerchair Football Week that we ran together with the WFA at the end of November attracted a great deal of attention across the country, bringing in new players, new teams and new clubs.

Do take a look at our fundraising pages to find out what fundraising events are on offer, and we’d encourage you to join #TeamOrange.

Thank you to all of you who fundraise for us, take part in fundraising events or volunteer for us in any way. We depend upon the support of people like you to fight muscle-wasting conditions.

Warm regards

Ruth Martin Editor, Target MD t: 020 7803 4836 e: r.martin@muscular-dystrophy.org tw: @RuthWriter Target MD is also available to read online: www.bit.ly/wTnEsn leading the way forward

12

Introducing our new

clinical fellow We recently awarded a Clinical Training and Research Fellowship to Dr Lizzie Harris, whose work at Newcastle University aims to improve diagnosis of limb girdle muscular dystrophy. Here we find out more about the project and why Dr Harris has chosen to specialise in the neuromuscular field.

Can you describe your research project?

Presently, approximately 25% of people with limb girdle muscular dystrophy do not receive an exact genetic diagnosis.

My project aims to use a new technique called ‘next generation sequencing’ to find mutations and genes which can cause limb girdle muscular dystrophy in people without a genetic diagnosis.

Genes are made up of DNA that carries the information needed to produce proteins and sequencing allows us to read this information. We all have around 23,000 genes, and using ‘next generation sequencing’ the information carried by all these genes can be read at once, rather than one by one, so mutations (like deletions or spelling mistakes) can be identified more quickly. We will use the technique to identify mutations in people we suspect have limb girdle muscular dystrophy but for whom we have been unable to provide a genetic diagnosis.

How do you reach a genetic diagnosis moment?

Current genetic testing is done on a gene-by-gene basis. A clinician will examine the symptoms of a patient and reach a possible clinical diagnosis. A muscle biopsy and a magnetic resonance imaging (MRI) scan may be taken to assist in this process. Once a clinical diagnosis is reached, the gene which is thought most likely to be causing the condition is tested and if a mutation is found then a genetic diagnosis can be given.

However, often the test results don’t show a mutation. In these cases the next most likely gene would be tested and so on. Because some conditions are caused by mutations in many different genes it can sometimes take several tests to identify the correct gene and to provide a genetic diagnosis.

In some individuals – around a quarter of patients with limb girdle muscular dystrophy – we are not able to give a genetic diagnosis because the condition is caused by an undocumented mutation or gene.

Newcastle is the national referral centre for limb girdle muscular dystrophy and so we perform diagnostic tests on people from around the UK. There are different levels of involvement we have: some people may be diagnosed by

www.muscular-dystrophy.org/research

their local neurologist and we do a genetic test to confirm the diagnosis. Some clinicians send in muscle biopsy samples which we analyse before choosing a genetic test. Some people visit the centre themselves where they receive a consultation and any genetic tests required.

How does next generation sequencing work?

Traditional sequencing allows the information carried by one gene or just a part of one gene to be read. Using ‘next generation sequencing’ the information carried by all an individual’s genes can be read at once. We take the DNA that makes up a person’s whole genome and cut it into small pieces using enzymes, which work like molecular scissors. We then use a new type of chemical reaction to analyse the DNA and read the information from all the pieces of DNA in parallel.

However sequencing the DNA is only the first step in the process of identifying a new mutation. The next step is the analysis of the sequence – where we sort out changes in the DNA that occur with no obvious consequences from those which are mutations that may cause disease. This is one of the challenges of ‘next generation sequencing’ – the technique generates vast amounts of data and powerful computers are needed to analyse it. Luckily we will be collaborating with researchers taking part in the neuromics project – a large EU project aimed at finding mutations which cause neuro-degenerative conditions. This collaboration is really important – it gives us access to the software and infrastructure they have developed to deal with this challenge.

Identifying more mutations and geneswhich cause limb girdle muscular dystrophy will give more people the opportunity to receive a genetic diagnosis. In the next few years it might be possible that ‘next generation sequencing’ will become a routine diagnostic tool, allowing us to test many genes at the same time to provide more patients with a faster and more accurate diagnosis. My project will also investigate some of the challenges of implementing the new technique into routine diagnosis.

13

people with muscular dystrophy with “aProviding precise genetic diagnosis not only means that they can access accurate information about what the future might hold and whether other family members might be affected, but also means that in the future they will be able to participate in clinical trials, for which a precise genetic diagnosis is likely to be a prerequisite.

“

Dr Harris

How does your project fit with the wider picture?

‘Next generation sequencing’ is being used in research into a wide range of rare conditions including neuromuscular conditions. Where there is a suspected genetic diagnosis which we haven’t been able to pinpoint, ‘next generation sequencing’ is becoming an important part of the process to identify new genes and mutations.

My project fits in at the beginning of the pipeline of research into limb girdle muscular dystrophy. Understanding the condition and its genetic basis can help us to develop new diagnostic tests for patients. It can also highlight which pathways and genes should be targeted by potential treatments and how approaches like gene therapy could be developed.

Why neuromuscular disorders?

I was interested in genetics right from school – probably because the human genome project was constantly in the news whilst I was doing my A-levels. When I studied at Newcastle University as a medical student, I chose to do an extra study option in genetics where I attended lots of Professor Bushby’s clinics. I thought it was a really exciting field and the dynamic environment inspired me.

In Newcastle, research is being performed which aims to improve our understanding of neuromuscular conditions, improving diagnostic techniques, and on developing and testing potential treatments. I feel very fortunate to be able to develop my interests in these areas further.

GRANT INFORMATION Project leader: Dr Elizabeth Harris Institute of Genetic Medicine, Newcastle

Conditions: Limb girdle muscular dystrophy and related muscular dystrophies

What will your typical day look like?

Duration:

I will be doing a mixture of work. I am part of a multidisciplinary team and I will be working closely with specialist nurses, neuromuscular physiotherapists and a care advisor.

I will attend a muscle clinic on one half day each week at Newcastle or at our peripheral clinics in Cumbria or Middlesbrough. That could be seeing children or adults with a whole range of neuromuscular conditions.

3 years, starting 2013

Total project cost: £ 180,000

Official title: High throughput sequence analysis to identify genetic causes of limb girdle muscular dystrophies.

leading the way forward

The remainder of my time will be spent working on my research project and how I spend that time will vary over the three years. At the moment I’m spending lots of time going through patient’s medical notes to try to identify those with symptoms similar to limb girdle muscular dystrophy and asking whether they would like to be included in the study.

How will the funding help you and what do you plan to do after the fellowship?

I am very grateful to the Muscular Dystrophy Campaign for funding my Clinical Training and Research Fellowship. The funding has meant I can take three years out of my clinical genetics medical training to develop a specialist interest in neuromuscular conditions and gain a PhD. Without the funding, this would not have been possible – I would only have been seconded to the team in the muscle clinic for a period of three to four months, which is obviously nowhere near the immersion I will achieve over three years here.

Additionally, in three years I will get experience of research, and of doing research myself, in an environment where that is an important part of the team’s daily work.

My research project will offer more people with limb girdle muscular dystrophy an accurate genetic diagnosis which can help us to provide the best standards of care and help the individuals to make informed decisions about family planning and lifestyle choices. My project may also help us to learn about the challenges of implementing ‘next generation sequencing’ as a routine tool, which could speed up genetic testing in the future.

After the project, I will go back to finish my speciality training in genetics which will take two years. I would very much like to keep an interest in neuromuscular conditions in those years and I hope in Newcastle that is something I will be able to achieve – the genetics centre is next door to the muscle centre!

After that, I’ll be looking for a consultant post, and again, hopefully somewhere where I can stay in the neuromuscular field. But to be honest that feels a long way down the line! www.muscular-dystrophy.org/research

What is a Clinical Fellowship?

Clinical Training and Research Fellowships (CTRF) are available to encourage clinicians into an academic research career in the field of muscular dystrophy and related neuromuscular conditions. 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.

15

Ask a Scientist

This issue’s question and answer page is a little different from usual. After the GlaxoSmithKline trial (which finished in September) failed to demonstrate that eteplirsen – a molecular patch for exon 51 of the dystrophin gene – was effective in boys with Duchenne muscular dystrophy, we worked together with patient organisations from around the world and with GSK and Prosensa to answer your questions.

How significant is this to a five-year goal of a workable drug?

T

he very nature of scientific research means it is often impossible to predict how research or clinical trials will proceed and what the results will show. It’s for this reason that we don’t try to predict how long it will take to develop effective treatments for the conditions we cover. What we can say though, is that researchers, clinicians and drug companies are working as quickly as they can to develop potential treatments.

Will all trials of drisapersen stop now?

T

he ongoing trials will not stop, but will be placed on hold and the participants will stop receiving drisapersen. However, while dosing has been placed on hold, scheduled visits, safety monitoring and assessments will continue. Efforts are underway by GSK to reduce assessments so that the burden to the boys is reduced while maintaining their safety.

What is the difference between a trial that is on hold and one that is stopped?

T

he dosing in the studies has been placed on hold pending a full review of the data. If the review shows that certain boys may benefit from treatment with drisapersen then it may be possible to continue dosing for those patients. If the studies were stopped then we could not restart the drug in a timely

manner. However GSK needs to further examine the individual cases before drawing any conclusions regarding a possible treatment benefit, and the decision to suspend medication will be revisited after completion of the planned analysis.

Will trials of different molecular patches stop now?

P

rosensa, the Dutch biotech company

testing molecular patches for exons 44, 45, 53 in clinical trials, has announced that those trials will continue.

We’ll watch out for more news and keep you up-to-date as we find out more. If you are taking part in a different trial and have questions about how the drisapersen results affect that trial, you should talk to the trial organiser or your clinician.

Why didn’t this trial work when other trials of drisapersen have?

W

hen GSK and Prosensa published results of their phase II trial earlier this year, they found a small effect which they were unable to completely confirm with their statistical tests. In this trial, the effect was even smaller, and the difference in results could be caused by many factors – for example a slight difference in the age of the boys or the distance they could walk at the start of the trial. The companies are now trying to identify these factors as they do their full analysis of the results to find out whether the trial may have worked in part.

My personal challenge In our last issue of Target Research we reported on the preliminary results of the exon skipping trial carried out by the pharmaceutical companies Prosensa and GlaxoSmithKline (GSK).

The results failed to show effectiveness for a molecular patch designed to skip exon 51 of the dystrophin gene.

To me the news showed that it is important to keep investing in high quality research and to continue the development of effective treatments for Duchenne muscular dystrophy and, of course the other conditions we cover.

It is also crucial that we support a broad range of approaches, because at this stage it is not clear which one will work and therefore we should not put all our eggs in one basket.

To support this research we need to keep raising funds and so I have decided to contribute, with my personal challenge.

In three weeks I will be cycling 330 miles through the heat and humidity of south Vietnam to reach Ankor Wat in Cambodia after little more than a week. I am not a cyclist and I wonder whether I will be able to do this – but when I think of all the families that we work with and support, I know we have to continue with our fight until there are effective treatments available for anybody who is affected by one of these devastating conditions.

Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign 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.

If you’d like to subscribe to the magazines, please post your details, together with a cheque for £18 made payable to ‘Muscular Dystrophy Campaign’ to Freepost Plus RTEE-SUBA-KXZT Muscular Dystrophy Campaign at 61a Great Suffolk Street, LONDON SE1 0BU: I wish to subscribe to Target MD and Target Research for one year, at a cost of £18.

I wish to make a donation of £

Gift Aid Declaration Using Gift Aid means that for every pound you give, we are able to reclaim back from HM Revenue and Customs the tax paid on it – helping your donation to go further.

Please tick the box below: Yes, I would like the Muscular Dystrophy Campaign to treat all gifts I have made in the past four years, today’s gift and all future gifts from the date of this declaration as Gift Aid donations.

No, please do not claim Gift Aid on my donations.

Please tick here if you do not want to receive occasional news, updates and other ways you can help by email, post or phone. We will never pass on your details to third parties, and you can unsubscribe at any time: www.muscular-dystrophy.org/contact

Call us on 020 7803 4837 or visit our website and subscribe online via Direct Debit at www.muscular-dystrophy.org/ targetmdsubscribe Alternatively, enter your details below.

Title

I confirm I have paid or will pay an amount of Income Tax and/or Capital Gains Tax for the current tax year (6 April to 5 April) that is at least equal to the amount of tax that all the charities and Community Amateur Sports Clubs (CASCs) that I donate to will reclaim on my gifts for the current tax year. I understand that other taxes such as VAT and Council Tax do not qualify. I understand the charity will reclaim 25p of tax on every £1 that I have given.

Date___________________________________________ Please ensure your full name is provided below.

Thank you.

Payment information: Method: credit card cheque To pay by credit card/debit card (Please complete the details below) Name (as written on card): Card type:

First name

Visa

Mastercard

Visa Debit

Switch/Maestro

Card no:

Surname Address

(Maestro only)

Expiry date: /

Start date (if applicable): /

Issue no (if applicable)

Security code

Postcode Phone Email Signature

Date

Target MD Issue 1 of 2014 Registered Charity No. 205395 and Registered Scottish Charity No. SC039445