Target Research 2 of 4 2012

Target Research Issue 2 of 4 2012

Newborn

screening Thought provoking

Is getting an early diagnosis by testing all babies at birth a good idea?

A must read

Psychology and muscle disease Research we’re funding to help people deal with daily challenges and get the most out of their lives

Can I take statins for my high cholesterol?

Experts answer this and other questions asked by you

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

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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.

Biopsy – the removal of a sample of tissue (such as muscle) from the body. The tissue is examined under a microscope to assist in diagnosis.

Carrier – an individual who has inherited a genetic mutation but does not have any symptoms. They have one normal and one abnormal copy of a gene which cause a genetic disorder. A carrier will usually remain unaffected throughout his or her life but may pass the faulty gene on to their children. Sometimes, such as in the case of female carriers of Duchenne muscular dystrophy, some symptoms such as mild muscle weakness may occur, this is called being a ‘manifesting carrier’.

Chromosome – cylindrical shaped bundles of DNA found in the cell nucleus. They consist of long, threadlike strands of DNA coiled upon themselves many times. We inherit 23 chromosomes from our mother and 23 from our father.

Creatine kinase (CK) – a type of protein found in muscle. Some forms of muscular dystrophy are associated with high levels of creatine kinase in a blood test because when muscles are damaged the creatine kinase leaks into the bloodstream.

DNA – (deoxyribonucleic acid) is the molecule that contains the genetic instructions for the functioning of all known living organisms. DNA is divided into segments called genes.

Dystrophin – the protein missing in people with Duchenne muscular dystrophy and reduced in those with Becker muscular dystrophy. Dystrophin is important for maintaining the structure of muscle cells.

Embryo – a fertilised egg that has the potential to develop into a foetus.

Enzyme – a protein that encourages a chemical reaction to occur.

Gene – a portion of DNA containing the instructions for the production of a specific protein.

Genes usually come in pairs, one inherited from each parent.

Genetic testing – the examination of an individual’s genes to identify defects causing a disorder.

Gene therapy – the use of DNA to treat disease.

This may involve introducing a new gene into the cells of the body to replace a defective gene.

Alternatively genetic material may be used to bind to a gene that already exists in the body to change how the DNA code is read.

IVF (in-vitro fertilisation) – a process by which the egg is fertilised by sperm outside the womb.

Mouse model – a strain or breed of mouse which has a disease that is similar to a human disorder.

Mutation – a change in a gene. Mutations can be passed on from generation to generation.

www.muscular-dystrophy.org/research

Nonsense 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.

Orphan drug – drugs intended to treat rare conditions that companies otherwise might not be able to develop for financial reasons. Drugs to treat conditions that affect less than 5 people per 10,000 are eligible.

Preimplantation genetic diagnosis (PGD) – a technique developed to enable people with a genetic condition running in their family to avoid passing it on to their children. It involves eggs being fertilised by sperm in the laboratory (IVF) and testing the resulting embryos to identify lowrisk embryos to start a pregnancy.

Prenatal testing – testing genetic conditions in a foetus before it is born. This is done by analysing the DNA in a sample of the fluid or tissue surrounding the foetus. The sample is collected by procedures called amniocentesis or chorionic villus sampling.

Phase 1 clinical trial – a small study designed to assess the safety of a new treatment and how well it’s tolerated, often using healthy volunteers.

Phase 2 clinical trial – a study to test the effectiveness of a treatment on a larger number of patients. Participants are usually divided into groups to receive different doses or a placebo.

Phase 2b clinical trial – a study which aims to find out how well the drug works at the dose determined in the phase 2a study.

Phase 3 clinical trial – multicenter 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.

Protein – molecules required for the structure, function, and regulation of the body’s cells, tissues, and organs. Our bodies contain thousands 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.

Steroids (corticosteroids or glucocorticoids) – a type of drug similar to natural hormones produced by the adrenal glands that reduce inflammation and suppress the immune response. They are often prescribed to boys with Duchenne muscular dystrophy. These are not “anabolic steroids” which are used illegally by athletes to build up muscle.

The Muscular Dystrophy Campaign is the leading UK charity focusing on muscular dystrophy and related conditions. We are dedicated to finding treatments and cures and improving the lives of the 70,000 adults and children affected by the conditions. We focus on funding world-class research, providing practical information, advice and support, campaigning to bring about change and raise awareness, awarding grants towards the cost of specialist equipment and providing specialist education and development for health professionals.

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.

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: hello@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

3 This thought provoking issue of Target Research tackles some hot topics and I hope you’ll enjoy reading about them. We are always keen to hear your views so please do tell us what you think and get involved.

Welcome

The main feature, which you can find on page four, is about newborn screening for neuromuscular conditions. This has been in the spotlight recently, especially for Duchenne muscular dystrophy and you can read about all the pros and cons in the article. Many of you filled out our survey on this issue and we have summarised the results, but if you missed the survey, it’s not too late to tell us what you think by contacting us (details below). We will continue to put forward the opinions of families as the issue is debated.

We also feature research we are funding at King’s College London that is looking at how the quality of life of people with muscle disease is affected by factors such as the way they cope with stressful situations and their beliefs about their condition.

Based on the outcomes of this research, plans are underway to test a new type of skills training to help people get the most out of their lives. See page 11 to find out more and for details of how you might be able to get involved in this research.

In the news this quarter we highlight progress being made towards preventing mitochondrial myopathy being passed on to future generations using a new type of IVF. We also report on new advances that are improving the diagnosis of neuromuscular conditions and announce exciting news of clinical trials starting and being planned.

Sadly this is my last issue of Target Research, at least for a while. I’m off on maternity leave and will be moving back home to Australia to have the baby. I’m sure you will get to know my replacement before too long and he or she will do a fabulous job of keeping you up to date with all the latest research news. I will be keeping a watchful eye from afar and cheering on the charity and researchers to keep making big strides forward.

Kristina Elvidge, Ph.D Editor t: 020 7803 4813 e: k.elvidge@muscular-dystrophy.org tw: twitter.com/kelvidge

Contents 4 Newborn screening – we consider the practicalities and ethics of newborn

screening for neuromuscular conditions 8 Research and clinical trials – news from the UK and around the world 11 Psychology and muscle disease – your thoughts are important 14 Ask a scientist – your questions answered by experts in the field 15 Breaking the Cycle – words of hope from Dr Marita Pohlschmidt,

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

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Early diagnosis is becoming an ever increasing concern for neuromuscular conditions as generally the earlier treatments are given to manage the condition, the more effective they are likely to be. This means that ideally patients need to be diagnosed before the muscles or nerves start to waste away and before symptoms start appearing. However, most people only go to the doctors for diagnostic tests when they notice symptoms of muscle weakness, and by then a lot of damage to the muscles and nerves may have already been done. One solution to gain an early diagnosis for genetic conditions is to test every baby shortly after birth but the practicalities and ethics of newborn screening are not straightforward and need careful consideration.

www.muscular-dystrophy.org/research

5 Most babies born since the 1960s in the UK will have had their heel pricked by a midwife in their first few days of life and a few precious drops of blood collected on a piece of card – a ‘Guthrie card’. These drops of blood are used to identify babies who may have rare but serious medical conditions.

The first condition to be screened for in this way was phenylketonuria (PKU).

About 1 in 10,000 babies born in the UK inherit this condition which means they are unable to process a substance in their food called phenylalanine.

If untreated they develop serious, irreversible, mental disability but if diagnosed early this can be prevented with a special diet.

Around the world different countries screen for vastly different numbers of conditions at birth. For example, most states in the US currently screen for more than 15 different conditions, and by contrast, most countries in the UK screen for just five: PKU, congenital hypothyroidism, sickle cell disorders, cystic fibrosis and medium chain acyl-CoA dehydrogenase deficiency (MCADD).

Who decides what to screen for, and how do they decide?

In the UK the National Screening Committee decides which conditions fit the criteria to be included in the newborn screening programme.

Generally the committee looks for three things: • There should be a ‘cure’ available that can be given from when symptoms appear • The costs of newborn screening must outweigh other options for improving current care procedures • Appropriate standards of care

and counselling must be in place for diagnosed families.

Newborn screening for Duchenne muscular dystrophy Screening newborns for Duchenne muscular dystrophy has been tried in 17 different locations around the world since 1977. However, the only place still maintaining a newborn screening programme for Duchenne muscular dystrophy is in the US state of Ohio. So it is safe to say that newborn screening for Duchenne has been fraught with difficulties.

How is the test for Duchenne muscular dystrophy done?

The test looks for the presence of creatine kinase (CK) in dried blood spots collected on Guthrie cards; no extra blood needs to be collected.

CK is a protein found in muscle but when the muscles are damaged due to disease or injury it leaks into the bloodstream. Once a positive CK result has been obtained from the original Guthrie card test, it is repeated six to eight weeks later since there is a risk of false positives due to the natural trauma associated with some births. If the levels are still high in this repeated test, this could indicate several different types of muscular dystrophy but Duchenne muscular dystrophy is the most common cause. Genetic testing is then used to confirm a diagnosis of Duchenne muscular dystrophy.

To screen or not to screen A Duchenne muscular dystrophy newborn screening programme existed in Wales for 22 years until December 2011. It was stopped due to technical problems that impacted on the accuracy of the test. The main issue relates to the requirement for diagnostic laboratories to have what is called an ‘external quality assurance’ scheme for each diagnostic test. This involves swapping samples with other laboratories and making sure that each laboratory is consistently obtaining the correct result. But with so few laboratories around the world conducting the dried blood spot test for Duchenne muscular dystrophy, this became impossible.

The UK National Screening Committee does not currently recommend newborn screening for Duchenne muscular dystrophy because it does not meet their criteria for the introduction of a new test.

There are many pros and cons of newborn screening and these are presented in the table overleaf. The main reason spurring on a group of clinicians in the UK to address the concerns raised by the UK National Screening Committee relates to giving boys early access to treatments to manage the condition such as steroids and physiotherapy. Currently the average age of diagnosis of boys with Duchenne is four, with some boys not diagnosed until as late as 10 or 11

years of age. On average there is also about a 2.5 year delay between parents noticing the first symptoms and telling their GP, to gaining a diagnosis and starting treatment. Not only is this a stressful time for parents, implementing the recommended standards of care to manage the condition is delayed.

Asking families what they think With all of these challenges, the Muscular Dystrophy Campaign, in partnership with the Duchenne Family Support Group and Action Duchenne, decided to conduct a survey to ask families affected by Duchenne muscular dystrophy for their opinion.

“The sooner you know about the condition the sooner you can manage it. The sooner you manage it, the better quality of life the child will have.”

In total, 255 people from the UK participated in the survey, 17 of whom were from Wales and had participated in the newborn screening programme for Duchenne muscular dystrophy. We wanted to know if people supported the introduction of a newborn screening programme now, in the absence of curative treatments. So we asked: “There is currently no effective treatment available to prevent the development of symptoms in boys with Duchenne muscular dystrophy; however, they can be given steroids at two to three years of age to delay the onset of symptoms. In this situation, would you support the idea of newborn screening for Duchenne muscular dystrophy?”

Approximately 82 percent of parents said yes, 5.5 percent said no and 12 percent didn’t know. Comments in favour included “The sooner you know about the condition the sooner you can manage it. The sooner you manage it, the better quality of life the child will have.” Others would only support newborn screening for family planning reasons.

We also asked “Would you have preferred to have known just after your child was born that they had Duchenne muscular dystrophy, or later on when you first noticed something was wrong?” 53 percent of parents said they leading the way forward

6 would prefer to know soon after birth, 28 percent at signs of symptoms and 19 percent didn’t know.

Those in favour of knowing soon after birth felt it would have helped them to plan for the future, plan future pregnancies and access the full range of therapies. Comments included: “As soon as possible would be best because you can be prepared for what changes you will have to make for your family life.”

Some felt they could have been better parents had they known earlier: “Speaking to other Mums who did not have the diagnosis early, they felt guilty, thinking their child was lazy when they were tired due to their condition and sorry that they reprimanded him at times when he was not at fault.”

Others would have liked to have known at birth because they found getting a diagnosis later on very stressful: ‘I personally would have liked to have known soon after birth, because for me, feeling something was wrong and always pressuring my GP and health Potential advantages of newborn screening for Duchenne muscular dystrophy Specialist care can be provided earlier to manage the symptoms eg. physiotherapy for tight joints, heart complications can be screened for and monitored and steroid treatment started at the optimal stage.

Support for boys with learning difficulties can be provided early, lessening impact on education Allow parents to make choices about having more children; they may wish to take advantage of prenatal or preimplantation genetic diagnostics to prevent having another child affected by Duchenne muscular dystrophy Give families time to come to terms with the diagnosis and plan for the future before symptoms appear Allow clinicians to monitor in detail the natural progression of the earliest symptoms of Duchenne muscular dystrophy in a large number of boys - a reference point to measure the benefit of therapies against and allow decisions to be made about the best time to start treatments such as steroids.

Challenges of newborn screening for Duchenne muscular dystrophy Such a devastating diagnosis can disrupt the bonding between parents and their newborn baby and seriously affect family stability, especially if appropriate support isn’t available Some families might prefer to have several years of ‘blissful ignorance’ before diagnosis, especially if there currently isn’t a cure Support and information given to families before, during and after diagnosis needs to be improved Support is currently not in place, or poorly co-ordinated for families after a diagnosis The CK test is not specific for Duchenne muscular dystrophy – it can detect some more rare, and often more mild muscular dystrophies such as Becker muscular dystrophy and limb girdle muscular dystrophy. Symptoms may not start until adulthood, so knowing the diagnosis throughout childhood may be undesirable The accuracy of the test needs to be improved. There is a relatively high risk of a false negative result – in Wales one in five boys with Duchenne muscular dystrophy was missed by the screening programme. These boys may not be diagnosed until late because it is assumed that Duchenne muscular dystrophy has been ruled out www.muscular-dystrophy.org/research

visitor for a referral was a very difficult time for me.”

Diagnosis later when symptoms arose was preferable to 39 of the 139 people who answered this question. This was largely because they enjoyed the stressfree time prior to diagnosis: “We had six wonderful years of blissful ignorance in which to enjoy our two young boys” and “Not much point knowing until a cure is found – it won’t make any difference” .

“We had six wonderful years of blissful ignorance in which to enjoy our two young boys” Several people commented that the timing of newborn screening was wrong: “I feel newborn is too early and at signs of symptoms is too late. It steroid treatment can be given as early as 2-3 years old, then testing may be better around then,” and “knowing soon after birth could rob a child of some ‘normal’ interaction and bonding with family”.

If however an effective treatment were available for a newborn baby immediately following diagnosis, that could slow muscle-wasting, a resounding 97 percent of those surveyed would support newborn screening. One parent commented “(I would support it) whole heartedly.

Currently knowing there is no treatment for DMD is similar to telling parents their child has an incurable cancer. Whereas if there is a known treatment then the sooner diagnosis is made the quicker treatment can start.”

However, parents still reiterated their concerns about the necessary support being available at diagnosis. This was mirrored in the responses from families in Wales who participated in newborn screening for Duchenne muscular dystrophy, many of whom said there was a lack of support and information throughout the diagnostic process: • Only 40 percent of respondents felt they received enough information about the heel prick test when making a decision to participate in the screening • Twenty nine percent were unaware that their baby was screened for Duchenne muscular dystrophy • Fifty percent said that the consent process could be improved

7 • Only 33 percent felt they received enough professional support during the diagnosis process with many being left to find out information themselves on the internet and from charities • However in their comments several respondents praised the help they received: “I cannot fault the support that we had at the time, nor the support since”.

To follow up on this, we asked respondents from all over the UK what information they thought should be provided to parents to help them make the decision on taking part in Duchenne muscular dystrophy newborn screening if it were offered, and by who, when and how. All of these responses will be fed into the planning process if a test is to be introduced in the future.

The way forward The UK Newborn Screening Committee allows new evidence to be submitted each year in support of introducing a new test. To work towards this, several initiatives have begun.

Firstly, researchers and clinicians around the world have joined forces to work towards improving the newborn screening test for Duchenne muscular dystrophy. They are working together on a standardised, more accurate test for introduction internationally in the future. Such a test will take time to develop and implement, so it is important that they start now.

It has been suggested that it may be time for the UK Newborn Screening Committee to look at updating its criteria for the introduction of a test – these have not changed in the past 40 years. Thanks to the support from the Muscular Dystrophy Campaign the All Party Parliamentary Group for muscular dystrophy in the House of Commons is currently conducting an inquiry into newborn screening for Duchenne muscular dystrophy, having taken evidence from clinicians, researchers and families living with the condition.

MPs and Peers will publish their findings later in the year.

Although Duchenne muscular dystrophy is not currently curable, it is most certainly treatable. There is evidence that better clinical

management of the condition earlier in life can improve quality and length of life. This evidence needs to be consolidated by examining the data that already exists worldwide from boys diagnosed early. For example, showing that the impact of learning difficulties on the lives of boys with Duchenne muscular dystrophy can be lessened or even prevented by early diagnosis, would strengthen the case for newborn screening.

Through the results of our survey and ongoing consultation we want to learn from the experience of families in Wales, and families all over the UK who have first hand experience of Duchenne muscular dystrophy. This will inform policy makers and ensure that the infrastructure is in place to support families before, during and after diagnosis if a newborn screening programme is introduced. Of vital importance would be an appropriate psychosocial network which might provide help with emotional, personal, family, financial, employment and/or social needs.

Newborn screening for Duchenne muscular dystrophy remains a controversial topic and many families have valid concerns about its introduction, but we feel that it is timely to look into the issue now and start to address the challenges. This will be particularly important if the potential new treatments currently in clinical trial turn out to be as effective as we hope they will be. Having a newborn screening programme in place would allow doctors to study the progression of the earliest symptoms in a large number of boys, identify when it might be best to start treatment and plan a clinical trial to determine if early treatment is beneficial.

Links... w: www.labs.gosh.nhs.uk/about-us/news/ pompe-disease If you have any questions or comments about newborn screening please contact us: e: research@muscular-dystrophy.org t: 020 7803 4813 With your permission, we will collate your comments to feed into the current inquiry going on in Parliament.

Improving diagnosis of Pompe disease Pompe disease is not included in the UK newborn screening programme, but there is a targeted screening programme – dried blood spots are only collected and tested from babies showing signs of the condition.

Pompe disease affects about 1 in every 40,000 babies. It is caused by a deficiency of the enzyme called acid alpha-glucosidase (GAA) which breaks down glycogen (a form of sugar) in muscle cells. This leads to a build up of glycogen in the cells which causes muscle weakness affecting mobility and breathing. Without treatment, babies with the most severe form of the condition die before the age of one. Less severe forms can occur at any age and can also be detected in the dried blood spot test at birth. These individuals may not have any symptoms until adolescence or adulthood so there are important ethical considerations with identifying them as newborns. For this reason, Pompe disease is not included in the screening programme for all babies.

In 2006 a treatment called Myozyme became available which consists of artificially produced GAA enzyme which is injected directly into a vein.

Myozyme has been shown to be effective, leading to a considerable improvement in symptoms and survival. Early diagnosis is vital so that treatment can begin before irreversible muscle damage has occurred.

In the past, Pompe disease was diagnosed by taking a skin or muscle biopsy and clinicians were often reluctant to subject babies to such an invasive test, especially since Pompe disease is so rare. A diagnostic programme was recently introduced at Great Ormond Street Hospital in London which aims to improve early diagnosis and treatment of the condition. Since the new dried blood spot test is easy and quick, clinicians are urged to test any babies that appear floppy, have delayed motor development or have difficulty feeding or breathing. An extensive education programme has been launched to educate doctors and other clinical staff to be on the lookout for the symptoms of Pompe disease. The dried blood spot test is also carried out at Guys Hospital London, and hospitals in Manchester and Glasgow. leading the way forward

mitochondria and these genes only affect how the mitochondria work.

Research

news

Progress made to prevent inheritance of mitochondrial myopathy A new £5.8 million Wellcome Trust research centre will be set up to continue research we have funded in Newcastle over the past 11 years. This research led by Professor Doug Turnbull involves a type of IVF to prevent mitochondrial diseases being passed from mother to child. This technique has proven successful in the laboratory but further research is required before it can be tested in a clinical trial and this can now go ahead at the new centre in Newcastle.

Mitochondrial diseases are caused by problems with the mitochondria - the batteries that power the cells in our bodies. It is estimated that 3,500 people in the UK have a mitochondrial myopathy, a group of mitochondrial

diseases which, in the most severe cases, can cause debilitating and lifethreatening muscle weakness.

The proposed procedure uses IVF to fertilise the egg of a woman affected by mitochondrial disease with her partner’s sperm. The genetic material of the fertilised egg that would determine the characteristics of the child (the chromosomes) would then be transferred to an egg donated by a woman who has healthy mitochondria.

The donor egg would first have its own chromosomes removed.

More than 99.9 percent of the genetic make-up of the resultant embryo would come from the parents and these 23,000 genes are the ones that determine our personal characteristics.

A tiny piece of DNA (13 genes) would be inherited from the donor’s Unfertilised donor egg with healthy mitochondria

Egg with abnormal mitochondria fertilised by IVF

Under the current law, researchers are allowed to investigate this technique in the laboratory using eggs and embryos donated to research but they are only allowed to keep the embryos alive for up to 14 days. For this technique to be brought into clinical practice, a change in the law is required to allow the resulting embryo to be placed into the mother’s womb.

The Government has asked the Human Fertilisation and Embryology Authority (HFEA) to seek public opinion about the use of such IVF techniques. The HFEA will bring together members of the public, policy makers and scientists to discuss the social and ethical issues raised by this new technique. An important aspect of the consultation will be to communicate the complicated science involved to the public and raise awareness of its implications. The public dialogue will start later this year, guided by a group of experts which will oversee the process. The Muscular Dystrophy Campaign is working with the HFEA to ensure the patient voice is represented.

If you are directly or indirectly affected by mitochondrial disease and would like to join a panel to voice your opinions on this topic, please contact us.

Our research at the forefront of genetic diagnostics Scientists at The University of Nottingham funded by the Muscular Dystrophy Campaign have used ‘next-generation DNA sequencing’ technology to correct the diagnosis of a patient with muscular dystrophy.

normal mitochondria

abnormal mitochondria

Pronuclei containing nuclear DNA (chromosomes) transferred to donor egg

Donor egg with nuclear DNA removed

Embryo with the nuclear (DNA) of the parents and the mitochondria from the donor egg

The study led by Professor Jane Hewitt focused on an individual who had originally been diagnosed with facioscapulohumeral muscular dystrophy (FSHD). However, when the researchers studied her DNA more closely, they found several inconsistencies and realised that she was highly unlikely to have FSHD. They could therefore have chosen to individually test a small number of genes that are known to be involved in other muscular dystrophies one by one, which can be a laborious and time consuming process and would have risked missing the mutation.

9 Instead, they used a machine that is currently revolutionising the field of human genetics: A ‘nextgeneration DNA sequencer’. Rather than just reading the code of a single gene at a time, these machines can simultaneously decipher all 20,000+ genes of the human genome. This has the advantage of almost guaranteeing to examine the DNA change causing the condition but also poses a serious challenge: human DNA is quite variable from one person to the next. Therefore, reading the genetic code of all genes will always identify tens of thousands of harmless ‘spelling differences’, which determine each person’s unique characteristics.

The Nottingham researchers approached this problem by using different data filters to carefully narrow down the DNA ‘spelling differences’ to those that could be causing the muscular dystrophy. This led them to find a genetic change known to cause limb-girdle muscular dystrophy type 2A. This gave the patient, for the first time, a precise genetic diagnosis.

This study demonstrates the power of next-generation sequencing as a diagnostic tool. While health services like the NHS will likely adopt similar technologies in the future, these methods are still developing and changing rapidly. Researchbased case studies such as this one provide important guidance for other researchers and prove the feasibility of these methods.

A precise, correct diagnosis is important because it enables doctors to give a more accurate prediction of how the condition will progress, which enables patients to make more informed choices on life decisions, including family planning. Importantly, if treatments such as gene therapy become available in the future, a precise diagnosis will be required so that patients can access the appropriate treatment for them.

(If you would like to learn more about next generation DNA sequencing please see the December 2010 issue of Target Research) Muscle stem cell controller found Research we funded at Barts and The London School of Medicine and

Dentistry has discovered that a gene called ‘Bmi1’ plays a crucial role in controlling the activity of muscle stem cells.

Muscle is repaired after injury by stem cells and the main type is the ‘satellite cell’ which sits on the outside of the muscle fibres. In uninjured muscle these cells are in a dormant state, but are awakened by muscle damage and quickly multiply to repair and replace the damaged muscle.

In other tissues in the body, such as the skin, the Bmi1 gene is involved in controlling the activity of the skin stem cells, so the researchers set out to investigate if Bmi1 is also important for muscle stem cells.

The researchers led by Dr Lesley Robson first showed that the Bmi1 gene is normally active in both human and mouse satellite cells. They then studied mice that lacked the Bmi1 gene. They found that these mice had smaller muscle fibres and were less able to repair muscle, especially after repeated muscle injury. In addition, mice with Duchenne muscular dystrophy and also lacking Bmi1 had smaller muscle fibres and were less able to regenerate damaged muscle.

The increased understanding of how the regeneration of damaged muscle is controlled is key for the future development of new therapies aimed at repairing the damaged muscles of people with muscle-wasting conditions.

New gene causing congenital myopathy found UK researchers have collaborated with scientists in Germany and Egypt to discover a new gene causing a rare type of congenital myopathy. They examined the DNA of 82 children who were all born with similar symptoms – difficulty breathing caused by paralysis of the diaphragm muscle, floppy and weak muscles especially in the arms, difficulty swallowing and they were found to have no reflexes. Other neuromuscular conditions such as spinal muscular atrophy had already been ruled out.

The researchers found that 10 of the children from five families had changes to a gene called MEGF10. The congenital myopathy affecting these children was subsequently named

EMARDD (early onset myopathy, areflexia, respiratory distress and dysphagia).

Further study of the MEGF10 gene in mice showed it contains the instructions for the production of a protein that is essential for the function of muscle stem cells. The muscles of the children with EMARDD were also examined under the microscope – they contained no MEGF10 protein and the muscle fibres were small with few muscle stem cells.

The authors of the paper commented that understanding the cause of EMARDD has identified potential targets for the development of possible treatments in the future.

We are currently funding further research in Professor Francesco Muntoni’s laboratory at University College London to search for more genes that cause congenital muscular dystrophies and myopathies so that more families, like the five in this research study, can gain a genetic diagnosis.

Understanding FSHD Scientists in the USA have brought us one step closer to understanding the complicated molecular mechanisms that underlie facioscapulohumeral muscular dystrophy (FSHD). It has been proposed that a protein called DUX4 that is produced in people with FSHD causes the symptoms of the condition by disrupting the control of other genes. This new study pin-pointed more than 1,000 genes were switched on, and over 800 genes were switched off

by DUX4. Some of these genes play a role in the immune response and this could explain some of the inflammation observed in the muscles of people with FSHD. This new research therefore confirms DUX4 as a possible therapeutic target for future research and scientists are already working on ways to block the production of DUX4. In addition, understanding what genes and biological processes within the muscles are affected by the production of DUX4 may shed light on new ways that we may be able to intervene and alleviate the symptoms of the condition.

leading the way forward

10

News in Brief

Study to look into falls in people with inclusion body myositis Researchers in London have embarked on a study to better understand falls in people with inclusion body myositis (IBM) and if physiotherapy could help prevent them. They are calling for people with inclusion body myositis to help with the research by filling out a survey. If you would like to take part please contact Liz Dewar via email: liz.dewar@uclh.nhs.uk or phone: 020 344 88038.

Clinical trial plans announced for utrophin drug for Duchenne Oxford based drug discovery company Summit Corporation has outlined their plans to test a drug for Duchenne muscular dystrophy. It is anticipated that a phase 1 trial in healthy adults will start soon and results should be available before the end of this year.

The drug called ‘SMT C1100’ is designed to increase levels of utrophin protein in the body which may be able to compensate for the lack of dystrophin in these boys. It may also be applicable to individuals with Becker muscular dystrophy who have reduced levels of dystrophin in their muscles, but this has not been studied in detail as yet.

A successful outcome from the phase 1 trial could lead to a phase 2 study in Duchenne muscular dystrophy patients starting in 2013.

New type of muscle stem cell identified Researchers in Paris have identified a new type of muscle stem cell - called ‘progenitor interstitial cells’ (PICs). They can be removed from the muscles of very young mice and grown in the laboratory, and are able to form new muscle when they are reintroduced into the damaged muscles of mice.

The researchers showed that PICs can repair muscle as efficiently as satellite cells, the professional muscle stem cells.

This work has identified a new source of stem cells in the muscle that may have potential for the development of therapies for muscle disease in the future. However, whether PICs are present in adult muscles and contribute to their regeneration in muscle disease, are all questions that need further study.

Ataluren for Duchenne extension trial PTC Therapeutics has said that the extension trial will start in centres in the UK, Europe, Israel and Australia between March and June 2012. The trial is for boys with Duchenne muscular dystrophy who have a DNA change called a ‘nonsense mutation’ and who previously participated in the phase 2b trial of ataluren.

www.muscular-dystrophy.org/research

Greetings from Target MD, our charity’s lifestyle magazine that, along with Target Research, makes up our quarterly magazine package.

Our supporters have told us many times of their frustration in getting accessible housing, or in getting their homes adapted to meet their family’s changing needs. Many families have called on our advocacy service to help them deal with difficult housing situations. You’ll see that our April edition of Target MD has housing as its central theme, and we bring you information and advice about adapting your house, or about challenging your local authority to help you get the housing that you need.

Read all about our Make today count national fundraising initiative that saw 100 people skydiving and 25 bucket collections taking place across the country for us. Social media buzz throughout the day kept our community involved in the activities which brought in more than £40,000 for research to find effective treatments and cures for Duchenne muscular dystrophy.

If you don’t yet subscribe to our magazine package, may I encourage you to do so? For just £18 a year, you’ll get both magazines, plus the regional fundraising insert, four times a year.

Gene therapy clinical trial for spinal muscular atrophy started Isis Pharmaceuticals has announced that it has started a phase 1 clinical trial of an antisense oligonucleotide (AO) drug called ISIS-SMNRx in patients with spinal muscular atrophy (SMA). This safety trial based in the USA will test the drug in 24 children with SMA. AOs are small pieces of DNA that can bind to a specific gene and change how the code is read. This can be considered a type of gene therapy. AOs are currently in phase 3 clinical trial for Duchenne muscular dystrophy. The commencement of this trial is very exciting because it is the first time that a gene therapy approach has been tested in patients with SMA.

Hello from Target MD!

If you have any ideas or feedback about any of the articles or future articles you’d like to see in Target MD, please do get in touch.

I’d love to hear from you.

Links...

Back issues of Target Research w: www.muscular-dystrophy.org/research/ target_research_magazine If you have any questions about this or any other research, please contact us: t: 020 7803 4803 e: research@muscular-dystrophy.org

Ruth Martin Editor, Target MD

Target MD is also available to read online: www.bit.ly/wTnEsn

11

Psychology and muscle disease: your thoughts are important

By Christopher Graham Institute of Psychiatry, King’s College London

Since 2008 the Muscular Dystrophy Campaign has been funding research at King’s College London into the quality of life of people with muscle disease and how this might be improved.

Here Christopher Graham, the PhD student we currently fund on this project, updates us on his research conducted under the guidance of Professor John Weinman (Institute of Psychiatry, King’s College London) and Dr Michael Rose (Consultant Neurologist, King’s College Hospital).

Back in October I attended the Muscular Dystrophy Campaign National Conference in Nottingham as part of a group of young researchers working on projects funded by the charity. It was a thoroughly enjoyable experience; meeting lots of people and families affected by muscle disease and talking with them about their experiences, as well as getting to know other researchers working in the area. We were presenting our work as posters so that anybody who was interested could see what we were doing and ask us questions about it.

However, upon arrival at the conference hall I discovered that the research I was doing was very different from the others. They were all working on the genetic and biological aspects of muscle disease, ultimately working towards the development of treatments, whereas my project aims to help people manage the day-to-day challenges that they currently face.

Going into the third year of our research project we have some exciting findings, and we are hoping to trial a new type of skills training to help people get the most out of their lives. leading the way forward

12

Why is quality of life research important?

Traditionally, the major focus of medicine has been treating disease and saving lives, with success measured in terms of cure or survival. However, as medicine has improved we have begun to appreciate that it is no longer sufficient to see survival or cure as the only goals in medicine.

Quality of life (QoL) is usually defined as a person’s evaluation of how life is compared to how they would expect it to be; put simply, it is how rich or ‘full’ someone feels their life is.

Measuring QoL is especially important for those with medical conditions where no effective treatments or cures currently exist. This allows clinicians to understand how patients’ symptoms directly affect their QoL and identify ways to improve QoL, even when the disease itself cannot be directly treated.

What affects your QoL? Firstly, it should be said that lots of things can affect QoL, whether you have a muscle disease or not.

Unsurprisingly, people who sleep better tend to have a better QoL than those who sleep poorly and experiencing a lot of pain or fatigue doesn’t help your QoL either.

However, some results which you might find surprising were returned from a large UK-wide questionnaire study that www.muscular-dystrophy.org/research

some of you kindly participated in two years ago. Over 220 people with various forms of muscle disease completed the questionnaire which showed that having more severe muscle disease is not as detrimental to QoL as one would expect. It seems that despite having very severe or advanced forms of muscle disease, many people in this position experience a very high QoL. Whilst this is heartening, the opposite pattern also appears to be true: unfortunately some people experience worse QoL than one would expect from their lower levels of disease severity. This means that the severity of symptoms does not really explain how rich or full someone perceives their life to be. Being psychologists we wanted to establish if the way people cope with stressful situations, their beliefs about illness or their mood might help explain these results, so we then set about investigating these factors.

The information recorded on the questionnaires showed that peoples’ ways of thinking about, and coping with, muscle disease were very strongly linked to their QoL. Taken together, this suggests that the beliefs someone has, and the way they cope with the challenges of muscle disease may play a stronger role in determining QoL than the actual severity of their symptoms.

From this point we wanted to understand the types of beliefs about

illness and ways of coping which are beneficial. So we interviewed a small group of people with muscle disease and asked them questions designed to get them to talk about how they have come to hold certain beliefs about their illness. This gave us clues as to how we might be able to encourage helpful beliefs and discourage unhelpful ones.

What does this all mean?

We wanted to devise a practical way of changing the unhelpful beliefs to the helpful ones we had identified.

We spent some months searching for the best way to do this. During this search we found a new type of approach which is showing exciting results with other medical conditions, such as epilepsy, diabetes and chronic pain. This method is called Acceptance and Commitment Therapy (or ACT). It focuses on teaching people ways to deal with the difficult thoughts and feelings which can occasionally hound us all, whilst also supporting helpful beliefs about illness.

ACT does this in a very interesting way; by asking people to embrace their negative thoughts rather than fighting them, to let thoughts go rather than analysing them and to live in the moment rather than in the past or the future. It fitted our purpose perfectly, and we have spent the last month tailoring this for people with muscle conditions.

13

The future So this brings me back to the beginning; the Muscular Dystrophy Campaign conference back in October 2011. One of the most lively and open conversations I had that day was with the mother of a young man with muscular dystrophy. She said to me “by suggesting that you can apply a type of psychological intervention to people with muscle disease don’t you risk making out that they have a psychological problem when thinking might be one of the few areas of life that isn’t affected by having muscle disease?”. This question stayed with me for a while, since, she had a point: people with muscle disease generally have spent more time in hospital than they would like, and mobility problems throw lots of unwanted challenges their way. Surely they don’t need to be told that their thinking is also affected by having muscle disease?

Thankfully, this is exactly what we are not doing and I was able to discuss this with her. What we aren’t saying is that because you have muscle disease, you will experience psychological problems and therefore you need psychological treatment. We know this is not true since many people experience high QoL even with the highest levels of disease severity. We also aren’t delivering a ‘treatment’ because that involves a person having a discernable problem in the first place. However, we

do acknowledge that having muscle disease can put a lot of unwanted obstacles in your path, and that having to deal with these difficulties can cause unwanted emotions, thoughts and unhelpful beliefs. What we now know is that the way you deal with the difficult thoughts can either help or hinder your QoL. As psychologists, our role is to find the best way to deal with unhelpful thoughts, feelings and beliefs and then set about helping people adopt more beneficial ways of thinking.

Our method of doing this is not about ‘thinking positive’ because this is unrealistic and it implies your challenges are trivial - like they don’t matter, or aren’t important. Also, our approach does not involve analysing your childhood or past, because we are not looking for past problems. It’s about teaching a set of skills and helpful ways of viewing illness that have proven beneficial for lots of different groups of people. In fact, aside from people with medical conditions, people have even applied this type of intervention to teenagers struggling with exam stress or anger management, and I myself, when faced with the anxiety of conference presentations, draw on lessons I have learnt from it.

Trial of the intervention So, having developed the intervention we are now at the most interesting point of our research programme: we

would like to test it to find out if it helps people.

The intervention aims to equip people with certain psychological skills.

By mastering these skills we hope that participants will experience an improvement in their own ability to deal with difficult thoughts, feelings and unhelpful beliefs, and that this will, in turn, produce improvements in QoL. We are going to deliver the psychological skills intervention in the form of an emailed booklet with some audio exercises and we hope that our participants will be able to master the skills set by spending one and a half hours a week, for three weeks, working through the exercises which we have set-up. A researcher will support participants with a weekly telephone call. We aim to start recruiting for this trial later this month.

Links...

If you would like to be involved in our forthcoming psychological skills training trial, or would like any further information about our research then please contact Chris Graham: t: 020 7188 9324 e: christopher.graham@kcl.ac.uk leading the way forward

14

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.

Q. I have been prescribed statins

for my high cholesterol, but the packet says you should ‘take special care if you or close family member have a hereditary muscle disorder’. I am a carrier of Duchenne muscular dystrophy; would it be ok for me to take this medication?

Gillian Knock, North Wales.

A. People with high levels of

cholesterol (a type of fat) in their blood are at increased risk of stroke, heart attack, and narrowing of the arteries to the legs. Some of the cholesterol in the blood comes from food, but most is synthesised in the body. Diet helps a little, but statins block the synthesis of cholesterol and have a potent effect on reducing cholesterol levels. Although there is some debate, the general consensus is that statins can provide a major health benefit, especially in those at high risk (e.g. in those with a family history of high cholesterol and those with diseases such as diabetes).

The three main types of muscle problems statins can cause are 1) About five to 10 percent of people taking statins complain of muscle aches and pains and often have raised levels of creatine kinase (CK) in the blood. This is a non-specific indicator of muscle damage and CK is increased in many muscle diseases. Many people can tolerate these symptoms, or they will improve with a lower dose of the same statin or changing to a different brand.

The symptoms resolve if the statin is stopped.

2) Extremely rarely (probably much

www.muscular-dystrophy.org/research

less than1 in 10,000 people) statins may cause rhabdomyolysis – over a few hours the patient develops widespread muscle pain and weakness due to extensive breakdown of muscle. The blood CK level is very high and kidney failure can occur which in rare cases is fatal. This serious complication is most likely to happen in people taking very high doses of statins, particularly in combination with other drugs.

3) We have recently found that very rarely statins can trigger a disturbance of the immune system and the body produces antibodies that attack the muscle (myositis). This causes weakness and an increase in the CK. It may resolve if the statin is stopped, but sometimes continues and it is necessary to use steroids (e.g. prednisolone) to bring it under control.

It is still controversial whether having a muscle disease or being a muscle disease carrier (such as women who are carriers of Duchenne muscular dystrophy) puts you at greater risk of statin-induced muscle problems. This is despite worldwide experience of treating many millions of people with statins, many of whom fall into this category. The most common muscle consequences of taking statins are muscle aches and pains and a rise in the blood CK – two of the most common features of muscle disease! There is very little evidence that the more serious complications of statins (2 and 3 above) are any more likely to happen in those with pre-existing muscle conditions or carriers. So, although simple precautions need to be taken,

in general such people can safely take statins and it would be wrong to deprive them of the potential benefits of these drugs.

On the basis of extensive personal experience, and the available medical literature, the approach that we advocate is to first check that there is a good reason for treatment with statins, and if so advise the patient of all of the above information so that they are adequately informed to make their own choice. If they decide to go ahead, then there are guidelines on dosage and monitoring that we recommend.

If you would like a copy of these to take to your doctor, please contact the Muscular Dystrophy Campaign and they will send them to you.

Dr David Hilton-Jones, Oxford Neuromuscular Centre Professor Mike Hanna, MRC Neuromuscular Centre, Queen Square, London.

Q. “Any interesting news on congenital MD?” @jonhollowell via twitter

A. Efforts to study the natural

progression of the various types of congenital muscular dystrophy (CMD) continue, providing essential information for a better understanding of the causes for rare types of CMD and preparing for potential upcoming clinical trials.

Regarding understanding what causes CMD, several new genes have recently been identified using the latest genetic technologies (see p 9 for one of these and Target Research magazine will report on the others in future issues).

There is a clinical trial planned to study a drug called omigapil in Ullrich congenital muscular dystrophy (UCMD) and merosin-deficient congenital muscular dystrophy (MDC1A). Omigapil is an oral drug, originally developed for the treatment of neurological disorders including Parkinson’s disease. Testing in mouse models for UCMD and MDC1A have shown that omigapil reduced the severity of symptoms in these animals.

This first clinical trial of omigapil for UCMD and MDC1A will be a ‘pharmacokinetic and safety study.’ This means that the aim of the trial is to

15 measure how much of the drug reaches the bloodstream (information which may help to determine the optimal dose for a subsequent clinical trial) and assess its safety.

A small number of patients will participate in this first trial which is proposed to be conducted at two study sites, one in the UK: Great Ormond Street Hospital (London) and the other in the USA: National Institute of Neurological Disorders and Stroke/ National Institutes of Health (Bethesda, Maryland). If the results of this trial are favourable, larger trials involving more patients would be planned.

While clinical trials for other types of CMD are not presently being planned, new therapeutic targets are currently being explored in the laboratory. These potential treatments are being tested in several animal models to assess their safety and potency. The outcome of these tests will tell us if they should be considered for clinical trials in the future.

Professor Francesco Muntoni, Director of The Dubowitz Neuromuscular Centre University College London.

Q. My son has congenital

myasthenic syndrome and was prescribed the drug 3, 4-diaminopyridine (3,4 DAP) which has now been withdrawn since the European directive to license it. The licensed version is 70 times the cost and doctors are not prescribing it. I have read the letter that consultants sent to David Cameron back in 2010 and wondered what progress has been made to allow doctors to continue to prescribe this drug.

Nigel Parker, Suffolk.

A. An unlicensed formulation of 3,

4-DAP has been widely and successfully used to treat Lambert-Eaton syndrome (LEMS) and some types of congenital myasthenia for decades. However, in December 2009 it was designated an orphan drug in the EU and granted a license for use in adults with LEMS. Since the introduction of the licensed drug, which is called ‘Firdapse’ there has been a great deal of uncertainty about the supply of 3, 4-DAP in the UK. Orphan drug law exists to motivate

pharmaceutical companies to develop and produce novel medicines for rare conditions which would likely be otherwise unprofitable. Orphan drug status gives the drug company the freedom to set their own price as long as profits are under an agreed threshold. In addition they have the exclusive right to supply the drug for ten years.

With 3, 4-DAP the main issue is the price difference between the two drugs. Whereas the cost of one year’s treatment with unlicensed 3, 4-DAP is typically less than £1000, the price of Firdapse on entry to the market was around 50-70 times more. This high cost means that some Primary Care Trusts have refused to pay for the drug because it doesn’t fulfil cost effectiveness criteria.

In October 2010 a group of clinicians wrote to the Prime Minister and the Secretary of State for Health to express concern that far from encouraging the development of new treatments orphan drug legislation is severely limiting the availability of existing treatments.

The letter was passed to the Department of Health who acknowledged that the current system of drug pricing does not promote innovation or access to the extent that they are looking for. In future there are plans to reform their pricing system so that there is a much closer link between the price the NHS pays for a drug and the value that new medicine delivers.

So the wider issue is being considered, but what does this mean for patients needing 3,4-DAP now? In late 2011 the main supplier of unlicensed 3, 4-DAP ceased manufacture for good. However, an alternative distributor responded to this by increasing production and assuring that they will hold six months stock in the UK at any one time to ensure continuity of supply. By and large most doctors are still prescribing the unlicensed drug and it has not been withdrawn. Anyone concerned about supply should discuss this with the doctor who usually prescribes the drug.

Dr Sarah Finlayson, Congenital Myasthenia Clinical Fellow, John Radcliffe Hospital, Oxford.

Breaking the Cycle As you might have read in the research news on page 8 the Wellcome Trust and the Medical Research Council (MRC) have decided to continue funding research into a technique called ‘pronuclear transfer’ (PNT). The technique was developed at Newcastle University

by Professors Doug Turnbull and Mary Herbert. The research was spearheaded by our charity and we have invested more than 1.2m into this technique over the last 20 years. This was fantastic news because it has great potential to develop into an effective treatment which probably comes close to a cure – it prevents the transmission of mitochondrial myopathy from mother to child.

However, ‘pro-nuclear transfer’ is not without controversy and reports in the media have carried headlines such as ‘Child with Three Parents’. The reason for this is that the faulty mitochondria containing less than 0.01% of the DNA of an affected egg will be substituted by healthy ones. At the moment the law does not allow such an embryo to be implanted into a woman’s womb and therefore the technique cannot be tested in clinical trial.

We are, however, pleased to learn that the government has initiated a consultation to seek public opinion.

But we now need to ensure that the facts are correctly communicated to the public, to our families and supporters and to policy makers. We are working closely with the Wellcome Trust and the MRC to ensure the media writes about this in a balanced way, avoiding scaremongering. We are keen to receive more feedback from you, our families, and if you have an interest in making your voice heard please contact us.

These are sensitive issues and our families should have a say whether this technique should be developed further, because ultimately they will carry the risks when enrolling into a clinical trial.

We will lead this campaign together with you - for you. We need to ensure that the Government makes the right decision that is based on facts and not on fear and uncertainty.

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

Come and climb Kilimanjaro with us 20 – 30 October 2012 Come and enjoy a peak experience with us in the beautiful heart of Africa. Climb to the top of Kilimanjaro and conquer the highest free-standing mountain in the world at 5,895m. While doing so, you’ll be making a huge difference to the lives of the 70,000 people we support around the UK who are affected by muscular dystrophy and related conditions.

Our experienced events team understands the huge commitment required from trekkers to complete this challenge, so in return for your amazing dedication, we will support you every step of the way, from the moment you sign up. We’ll send you a full training guide, fundraising hints and tips and a monthly newsletter to help keep you motivated.

To sign up or to find out more, contact Julia Selby on: t: 020 7803 4828 e: events@muscular-dystrophy.org w: www.muscular-dystrophy.org/kilimanjaro Registered Charity No. 205395 and Registered Scottish Charity No. SC039445