Target Research 2012 (3of4)

Target Research Issue 3 of 4 2012

Bench to Thought provoking

bedside An update on cutting edge research from our conference A must read

Clinical trials What’s happening right now?

Register now!

Join the newly launched myotonic dystrophy registry

Also inside‌read the latest research news from the UK and around the world and experts answer your questions

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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.

Animal model – a laboratory animal such as a mouse or rat that is useful for medical research because it has specific characteristics that resemble a human disease or disorder.

Biomarker – a biological substance found in blood, urine or other parts of the body that can be used as an indicator of health or disease. A biomarker may be used to help clinicians diagnose a condition and monitor how it is progressing, but can also be used to see how well the body responds to a treatment.

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

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

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

Exon – genes are divided into regions called exons and introns. Exons are the sections of DNA that code for the protein and they are interspersed with introns which are also sometimes called ‘junk DNA’.

Exon skipping – a potential therapy currently in clinical trial for Duchenne muscular dystrophy.

It involves ‘molecular patches’ or ‘antisense oligonucleotides’ which mask a portion (exon) of a gene and causes the body to ignore or skip-over that part of the gene. This restores production of the dystrophin protein, albeit with a piece missing in the middle.

Gene – genes are made of DNA and each carries instructions for the production of a specific protein. Genes usually come in pairs, one inherited from each parent. They are passed on from one generation to the next, and are the basic units of inheritance. Any alterations in genes (mutations) can cause inherited disorders.

Inflammation – the body’s reaction to injury or infection. It is a protective attempt by the body to remove whatever is causing the injury or infection (for example a splinter in your finger or a virus in your lungs) as well as initiate the healing process.

In vitro fertilisation (IVF) – a process by which eggs are fertilised by sperm outside the womb. The fertilised egg is then transferred to the patient’s womb to try to establish a successful pregnancy. mdx mouse – a mouse model of Duchenne muscular dystrophy. These mice have a mutation in the dystrophin gene - the gene that is mutated in boys with Duchenne. The muscles of these mice have many features in common with the muscles of boys with Duchenne muscular dystrophy.

Membrane – the barrier between the inside and outside of a cell or between two compartments of a cell. Membranes act like a skin to protect cells and control which substances leave or enter them.

Mesoangioblast – a type of stem cell that originates from the lining of blood vessels.

Mitochondria – the ‘energy factories’ of cells. They have their own DNA, inherited from the mother.

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

www.muscular-dystrophy.org/research

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.

Myostatin – a protein that helps mammals regulate muscle building, acting as a signal for muscles to stop consuming resources and stop growing. Scientists think that by blocking the activity of myostatin, it might be possible to build up muscle size and strength in people with muscle disease.

Neuromuscular junction – where a muscle fibre and a nerve meet.

Next generation sequencing – a cutting edge technology that allows researchers to ‘read’ the whole of an individual’s genome. Researchers have recently started to use it for finding new genes and diagnosing genetic conditions more accurately.

Nucleus – the control centre of a cell, which contains the cell’s chromosomal DNA. Phase 1 clinical trial – a small study designed to assess the safety of a new treatment and how well it’s tolerated, often using healthy volunteers.

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

Phase 3 clinical trial – a multicentre trial involving a large number of patients aimed at being the definitive assessment of how effective a treatment is prior to applying to the regulatory authorities for approval to make the treatment widely available.

Placebo – an inactive substance designed to resemble the drug being tested. It is used to rule out any benefits a drug might exhibit because the recipients believe they are taking it.

Protein – molecules required for the structure, function, and regulation of the body’s cells, tissues, and organs. Our bodies contain millions of different proteins, each with unique functions. The instructions for their construction are contained in our genes.

Randomised controlled trial – a clinical trial where treatments and placebo are allocated randomly to participants rather than by conscious decisions of clinicians or patients.

Riboflavin – a B vitamin that is found in a number of foods such as leafy green vegetables, milk and eggs. It is an essential nutrient for humans.

SMN protein (Survival Motor Neuron protein) – produced by the SMN genes and reduced in individuals with spinal muscular atrophy. This protein is necessary for normal motor neuron function.

Stem cells – cells that have not yet specialised to form a particular cell type, and can become other types of cell such as muscle cells. They are present in embryos (embryonic stem cells) and in small numbers in many adult organs and tissues, including muscle.

Translational research – the application of knowledge gained from scientific medical research in the laboratory to studies in humans.

Utrophin – a 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.

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 Before I get to talking about some of the topics we will be covering in this issue of Target Research, I should introduce myself! I’m Julia, and I’m the Head of Grants at the Muscular Dystrophy Campaign.

Now that Kristina is in back in Australia and enjoying being a new mum, I have been temporarily covering for her until Neil Bennett, our new editor, takes over.

Welcome

The main feature in this issue, on page 4, is a report on the fifth UK Neuromuscular Translational Research Conference held at the end of March. Our volunteer science writer, Dr Alexandra Dedman, brings us an update on the meeting, which was attended by 200 scientists and clinicians from around the UK and further afield.

It’s an excellent opportunity to get the scientists and clinicians together to share ideas as well as showcase some of the research we have funded. Alex gives us an overview on many different areas of research, including how new technologies are revolutionising the hunt for genetic mutations that cause rare diseases.

We are also featuring a clinical trials update in this issue. We get a lot of questions from families and individuals asking about treatments and at what stage of development they are. We try to keep everyone as up to date as possible with the Research News on our website, but we thought it would be great to give you an overview of what is happening right now. You will find all the latest on the exon skipping trials for Duchenne muscular dystrophy as well as news on how this technology could be used to treat other conditions.

In the news, we update you on the progress being made towards the consultation on whether to change the law to allow the use of an IVF technique to prevent the transmission of mitochondrial myopathy from mother to child. We also highlight some exciting new research on Duchenne muscular dystrophy that may lead to a therapy in the future.

I do hope you enjoy this issue of Target Research. Then it’s over to Neil, who will be picking up the torch for the next issue!

Julia Ambler, DPhil (Stand-in) Editor t: 020 7803 4812 e: research@muscular-dystrophy.org tw: @JAmblerMDC

Contents 4 Highlights from the fifth UK Neuromuscular Translational Research Conference – an update on cutting edge research 8 Research news – from the UK and around the world 11 Clinical trials – find out what is happening now 15 Ask a scientist – your questions answered by experts in the field

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

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Highlights from the Fifth UK Neuromuscular Translational Research Conference www.muscular-dystrophy.org/research

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E

xciting new technologies are being used to help diagnose and develop treatments for muscle and nerve disease. This dominated discussions at the fifth UK Neuromuscular Translational Research Conference that took place in Newcastle upon Tyne in March, and which brought together scientists and clinicians from around the UK as well as international speakers. Our science writer, Dr Alexandra Dedman, was at the congress and here she summarises the highlights:

The UK Neuromuscular Translational Research Conference, co-organised by the Muscular Dystrophy Campaign and the MRC Centre for Neuromuscular Disease, was first held in 2008. Its aim is to bring together top researchers for presentation and discussion of the latest research – helping to drive forward research and treatment of muscle and nerve disease. It is a great opportunity to encourage communication between scientists and clinicians and encourage them to work together and share resources.

The conference is held every year in London, Oxford, or Newcastle upon Tyne, and attracts hundreds of scientists, clinicians and industry partners working on muscle or nerve disease. This year, the International Centre for Life in Newcastle upon Tyne hosted the conference, which ran from Thursday 22 March to Friday 23 March.

The days were jam-packed, with two sessions every day addressing a different topic and creating a platform for researchers to present their latest scientific findings and ideas. These sessions attracted lively debate as for some this was the first time their new and exciting results had been presented. There were also more than one hundred posters to be discussed over morning coffee and lunch, with special ‘guided tours’ from eminent experts in the field.

How neuromuscular diseases develop Researchers from the UK, Italy and Germany came together on the first morning to present their latest research findings on the cause and development of neuromuscular disease. This kind of

basic research is essential – the more that is known about a disease, the more likely it is that new treatments can be developed. Much of this session focused on research to improve genetic diagnosis of disease; many families are still living without knowing the cause of their disease or how it will progress.

Finding the precise genetic cause can help patients and their families prepare for living with the disease, as well allowing them to make informed family planning choices. It can also be an important step in helping researchers to develop a therapy.

Prof Dieter Fürst from the University of Bonn presented results showing mutations in new genes they had found which may be a cause of myofibrillar myopathy. Meanwhile other researchers presented new findings helping to explain the genetic causes of mitochondrial disorders. Mitochondrial disorders can be caused by mutations in many different genes located either in the nucleus or in the mitochondria.

Not all of the genes involved in causing

leading the way forward

6 mitochondrial disorders are known and researchers are using new techniques such as next generation sequencing to find them so that more people can receive a diagnosis and increase our understanding about this complex group of conditions.

‘Bench to bedside’ medicine The afternoon session of the first day focused on new ways to bring research from ‘bench to bedside’, that is, how to push new findings forward into developing new treatments.

An interesting talk was given by Dr Katherine Klinger from Genzyme explaining the process behind developing treatments for Pompe disease, a metabolic disorder that causes a build up of sugars in the muscle. As Dr Klinger outlined in fascinating detail, developing new medicines takes a lot of people, a lot of time, a lot of money, and is always ‘harder than you think it is going to be’. Dr Klinger explained that it took 20 years of development to get a drug to the market for Pompe disease, and that even though it has been available since 2006, development of it has not stopped, as ‘there is always room to improve’.

www.muscular-dystrophy.org/research

Delegates also heard from Muscular Dystrophy Campaign-funded clinical fellow, Dr Regan Foley from the Institute of Child Health in London, about her success in using high-dose riboflavin to treat a neurological condition called Brown-Vialetto-Van Laere syndrome. Dr Rebecca Fairclough from the University of Oxford talked about the work from her Muscular Dystrophy Campaign-funded grant. She described how she and her colleagues had used a specially-developed drug screen to find small drug-like molecules which may be effective in treating Duchenne muscular dystrophy. The aim is to increase the amount of a protein called utrophin in the muscle.

Their previous work has shown that utrophin may be able to compensate for the lack of dystrophin protein in the condition. One of the drugs they found, called SMT C110, is now in phase I clinical trial.

The final presentation of the day was from Dr Dipa Raja Rayan at the Institute of Neurology, presenting promising results of an international clinical trial investigating the effectiveness of Milexetine in treating nondystrophic myotonia, a muscle disorder

characterised by difficulty in relaxing certain muscles. Milexetine is not a new drug; it was originally used to treat heart problems but is now no longer in clinical use. Preliminary results showed that patient stiffness, pain, weakness and tiredness all improved with Milexetine, with minimal side-effects.

Researchers are now pursuing orphan drug status for Milexetine. Orphan drug is the name given to drugs used to treat very rare diseases; if this status is granted, more money will be available for its clinical development to test its safety and effectiveness.

7 Next generation sequencing The morning of the second day focused on how researchers have embraced a new, cutting-edge technology called next-generation sequencing to help find mutations that may be so rare they only affect a very small number of families worldwide.

This technology is transforming the search for mutations in new genes; rather than reading just the DNA code of a single gene at a time, newly-developed machines can simultaneously decipher several genes or even all 25,000+ genes of the human genome. Recent advances are making next generation sequencing cheaper and more available to clinics and researchers, and presentations in this session focused on how it could be applied to diagnose muscle and nerve diseases more efficiently.

During this session, Prof Madhuri Hedge from Emory University in the USA explained that while this technology was a fantastic step forward, it did bring with it some challenges. This method of reading the DNA code produces huge amounts of data which can be difficult and expensive to handle, and it can also be difficult to verify whether a change in the DNA identified by this method is simply a harmless ‘spelling difference’, or a mistake that could be causing a disease. Furthermore, when reading the whole DNA code, genetic changes may be identified which are related to different disorders - this obviously throws up ethical dilemmas about patient information. Nonetheless, this technology is changing and improving genetic testing and diagnosis in the clinic. Prof Madhuri also talked about a new genetics database which has been set up in the US to help researchers handle the huge amount of new data being produced.

The session was wrapped up by Dr Gerald Pfeffer from the University of Newcastle who explained how his group used next generation sequencing to help find mutations which may cause a rare form of myopathy, present in only 16 families worldwide (three of which are in Newcastle). The Muscular Dystrophy Campaign is currently funding research projects using this technology to find mutations in new genes causing mitochondrial myopathies, congenital muscular dystrophies, periodic paralysis and the myotonias.

Stem cells The afternoon session on the second day focused on another hot topic - the use of stem cells to treat muscle disease. Several researchers presented new results showing potential benefits of stem cell therapies in animal models, and a longanticipated presentation came from Prof Giulio Cossu at the Institute of Child Health in London. Prof Cossu reported preliminary results from a small phase I clinical trial investigating stem cell therapy in the treatment of Duchenne muscular dystrophy. Prof Cossu tested, in six patients, a type of stem cell called a mesoangioblast that comes from the inner lining of blood vessels. The aim of the study was to establish if the therapy was safe, and to do this the researchers had to overcome several challenges. Thirty percent of the body is made up of muscle and you need to get stem cells to all the muscles throughout the body.

Mesoangioblasts have an advantage over other stem cell types in that they can easily cross from the blood to the muscle. Prior to the trial, Prof Cossu developed new techniques to harvest and grow the cells in the laboratory; however it proved difficult to get the cells from each patient to grow consistently. The trial has now finished and Prof Cossu was cautiously optimistic; none of the patients had any severe side effects and although the study had proved challenging, the information gathered should inform future stem cell trials.

All the sessions generated a great deal of discussion between delegates on the best way to drive forward translational research. Several recurring themes came out of these sessions: it is essential to know as much as possible about the cause of the disease before a treatment can be developed, and it takes a long time and a lot of collaboration between scientists, clinicians, industry, and regulatory authorities to bring a treatment to the patient, and the whole process must be flexible throughout, changing and adapting as new knowledge and technologies become available. One thing the researchers all agreed on was that this conference had helped to drive translational research in muscle and nerve disease one step further forward.

leading the way forward

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Research

news

New registry brings hope for families with myotonic dystrophy A new patient registry for individuals with myotonic dystrophy type 1, funded through a partnership between the Muscular Dystrophy Campaign and the Myotonic Dystrophy Support Group, has been launched. The new registry will allow clinicians and researchers to speed up the transition of treatments from the laboratory to the clinic by speeding up the recruitment process of people to take part in clinical trials and to better understand the condition.

Researchers have made considerable progress in recent years with the development of promising technologies that could provide the basis for potential treatments for myotonic dystrophy. To find out whether any of these new technologies can be used to treat the symptoms of the condition, they have to be tested in a clinical trial. Myotonic dystrophy, www.muscular-dystrophy.org/research

however, is a rare disease and one of the problems clinicians will face is in finding sufficient patients quickly enough to allow the start of a clinical trial without delay.

The registry, established under the lead of Professor Hanns Lochm端ller at Newcastle University, is a centralised database that contains the crucial information needed to find people suitable for clinical trials.

The information will also be used to develop standards of care and will give people a link to the research community, as well as the opportunity to access information directly relevant to their condition.

We are calling on everybody in the UK with myotonic dystrophy type 1 to come forward and register. You will be asked to fill in a short online questionnaire about your symptoms and family history. If you have limited access to the internet, you can phone the registry curator, Karen Rafferty (0191

241 8640) to request a paper copy of the form to be sent to you. All the data is stored in a secure server and is only accessible to appointed registry staff.

Inquiry into allowing treatment of mitochondrial myopathy In March 2012, the Muscular Dystrophy Campaign and the Association of Medical Research Charities (AMRC) jointly responded to a call for evidence from the Nuffield Council on Bioethics, which was conducting an inquiry into the ethical implications of developing emerging techniques to prevent the transmission of mitochondrial disorders. Our response emphasised how important it is to consider the concerns of patients and their families, and other public supporters of the research, in this important consultation and decision-making process. The resulting report concluded that further development of these treatments should take place and, if the development is successful, that

9 using these treatments to stop the inheritance of mitochondrial diseases – such as mitochondrial myopathies – would be ethically sound.

Research funded by the Muscular Dystrophy Campaign and led by Professor Doug Turnbull in Newcastle has developed a technique which involves IVF to prevent mitochondrial diseases being passed from mother to child. 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 tested in clinical trial, a change in the law is required to allow the resulting embryo to be placed into the mother’s womb.

As we reported in the previous issue of Target Research, the HFEA will lead a public consultation on this issue. The Nuffield Council on Bioethics report, along with the HFEA consultation and other sources, will inform MPs and peers as they debate the changes.

The Muscular Dystrophy Campaign has invested in research into this area for more than 10 years in hope of finding ways to prevent mitochondrial myopathies, for which there are currently no cures or preventative treatments. If the techniques are shown to be safe and effective, we are keen to see them obtain regulatory approval so that they can start to benefit families that currently have to make the difficult decision of either not having children or having children at risk of inheriting the disorder.

You can read our full response on our website. Alternatively, you can call or email us for a copy (contact details on p10).

New drug a potential treatment for Duchenne muscular dystrophy An international group of scientists, led

by Prof Gordon Lynch at the University of Melbourne, Australia, has shown that increasing the amount of a protein called heat shock protein 72 (Hsp72) can have a beneficial effect in a mouse model of Duchenne muscular dystrophy.

The lack of dystrophin in Duchenne muscular dystrophy leads to a series

of events that cause the muscles to weaken and waste. One of these events is a large increase in the amount of calcium inside the muscle. Small tears in the muscle membrane that arise through the lack of dystrophin allow calcium into the muscle from the outside environment. High levels of calcium are damaging and lead to chronic inflammation and breakdown of the muscle.

New gene causing congenital muscular dystrophy discovered Muscular Dystrophy Campaign grantee, Prof Francesco Muntoni, and an international group of scientists have discovered that mutations in a previously unknown gene can cause a particular form of congenital muscular dystrophy called Walker Warburg syndrome.

The researchers decided to investigate heat shock protein 72 (Hsp72), a protein known to be able to help cells regulate their calcium levels. Prof Lynch and his team used mdx mice (the mouse model for Duchenne muscular dystrophy) that were also specially bred to produce high levels of Hsp72 in their muscles. When compared to mdx mice that produced normal levels of Hsp72, these mice had less muscle breakdown, improved muscle strength and, importantly, less degeneration of the diaphragm (the breathing muscle). The researchers showed that this was owing to the fact that the muscles were being repaired more efficiently.

Walker Warburg syndrome (WWS) is a severe form of congenital muscular dystrophy that includes involvement of the eyes and brain. About half the people who are thought to have WWS do not have a genetic diagnosis, indicating that there could be several as yet unidentified genes implicated in causing this condition.

Since these initial results were promising, the team decided to test whether a drug, called BGP-15, that is known to increase levels of Hsp72 in humans, might show similar results.

BGP-15 is currently in clinical trial to treat diabetes. They tested the drug on a very severely affected mouse model of Duchenne muscular dystrophy, called the double-knockout (dko) mouse. BGP15-treated mice had decreased muscle breakdown and greater muscle strength than untreated dko mice. They also had less degeneration in the diaphragm which points to an improvement in their ability to breathe as well as an increase in lifespan.

These results highlight new targets that could be used to develop therapies for Duchenne muscular dystrophy.

Although this approach would not address the underlying cause of muscle wasting, it could help to prevent or delay some muscle damage occurring and may provide an additional benefit if it were combined with another treatment such as exon skipping. It is important to remember, however, that this research is still at a relatively early stage and has been done in animal models. Further work will have to be done before such a therapy can be taken to clinical trial.

Prof Muntoni and his colleagues studied the DNA of 11 individuals who have WWS but no genetic diagnosis. They used a combination of techniques, including cutting-edge technology called “next generation sequencing” to determine the cause of WWS in these individuals. The researchers determined that of the 11 individuals, seven appeared to carry mutations in the same gene. By studying the DNA of these seven individuals further the team were able to narrow down a small number of areas where the mutation might be located. Using next generation sequencing to “read” these areas of the DNA the team narrowed this down further to one candidate gene – the isoprenoid synthase domain containing gene (ISPD). Researchers do not yet fully understand what the function of this gene is, nor how mutations in the ISPD gene act to cause congenital muscular dystrophy.

This discovery represents real progress as this is the first time researchers have used this combination of techniques to determine the cause of a muscle disease.

It will allow a precise genetic diagnosis for a greater number of children with this condition and the technique may be used to help find the cause of other forms of congenital muscular dystrophy.

Having a precise genetic diagnosis brings many benefits for families, allowing them to plan for the future and make informed choices about family planning. Understanding more about the condition may also allow researchers to develop new therapies. leading the way forward

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News in Brief

Phase 3 clinical trial for Ataluren announced PTC Therapeutics has announced that they have now started a phase 3 clinical trial for ataluren in the UK, continental Europe, Israel, Canada and Australia. The 48 week trial to test ataluren in boys with Duchenne and Becker muscular dystrophy will be an open-label study open to individuals who previously took part in the phase 2b trial. Although the primary aim is to assess how safe and well tolerated the drug is over a longer time period they will also be carrying out some tests, such as the six minute walk test, to determine if ataluren has a positive effect on muscle function.

Research brings us closer to understanding the cause of spinal muscular atrophy Researchers In the US have uncovered further clues about why having low levels of the SMN protein causes the symptoms seen in spinal muscular atrophy (SMA).

They found that SMN controls the levels of a protein called plastin 3 (Pls3) so that it is present at a much lower level than normal in SMA. Using a zebrafish model of SMA, the team was able to demonstrate that the decrease in Pls3 was affecting the formation of specialised structures called neuromuscular junctions and was having a negative effect on the movement of the fish. While increasing the levels of Pls3 caused the zebrafish to swim and turn more frequently, it did not increase the lifespan of the fish. This is an important piece of research that has contributed to our understanding of exactly what is happening to the motor nerves in SMA. Understanding which proteins, other than SMN, are critical for the function and survival of motor nerves will help researchers to find therapeutic targets and in time develop more effective therapies.

New collaboration to support omigapil clinical trial for congenital muscular dystrophy Santhera Pharmaceuticals has announced a collaboration that will help to facilitate the smooth transition of omigapil from the laboratory through to the clinic. The pharmaceutical company has partnered with European consortium EndoStem for the upcoming clinical trial of omigapil.

EndoStem, which is co-funded by the European Union, aims to conduct clinical trials in muscular dystrophies using innovative new drugs and therapeutic approaches. Their focus is on regenerative medicine and involves trying to understand and harness the factors that control how muscles can repair and regenerate themselves following injury, in disease and in aging.

It is hoped that should the clinical trials provide a positive outcome, the collaboration between EndoStem and Santhera will ensure a commercialisation pathway for omigapil so that it could become widely available for patients with these conditions.

Links...

Hello from Target MD!

Greetings from all of us in the team that puts together Target MD, the lifestyle magazine for the Muscular Dystrophy Campaign.

Together with Target Research, this magazine makes up our quarterly magazine package.

We as a charity rely heavily on the support of our volunteers. We have so many people who, in so many ways, help us to fight muscular dystrophy and related conditions in the UK, on all fronts – through campaigning, fundraising, supporting our events, working in our offices, leading our committees and supporting our parliamentary work. There isn’t sufficient room in the magazine to acknowledge all the ways that volunteers work with us, but by reading through the extensive volunteering feature, we hope you will get an idea of their hard work and our deep appreciation of all they do.

We also pay tribute to two long-term and highly influential supporters of the charity, whose exceptional efforts have helped the charity to lead the way in research into effective treatments and cures for muscle-wasting conditions.

Lord Walton of Detchant and Lord Attenborough need little introduction; read about their work with our charity, on p18 of Target MD. And, of course, there’s our latest campaigning, research and fundraising news, with wonderful photo spreads of our running events in London, Cambridge and Oxford.

Do let me know if you have any thoughts or comments about the magazine, or any ideas for future editions. We do always want to bring you the news and stories you want to read.

I’d love to hear from you.

Back issues of Target Research w: www.muscular-dystrophy.org/research/target_research_magazine Subscribe to our eNewsletter for monthly updates on research w: www.muscular-dystrophy.org/enewsletter If you have any questions about this or any other research, please contact us: t: 020 7803 4812 e: research@muscular-dystrophy.org www.muscular-dystrophy.org/research

Ruth Martin Editor, Target MD Target MD is also available to read online: www.bit.ly/MfpNQW

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Clinical trials Bringing treatments into clinical practice

Since the beginning of the 1990s when DNA technology made a huge leap forward with the introduction of new techniques, more than 100 genes have been found that can cause muscular dystrophy or a related neuromuscular condition. The knowledge has been vital in enabling researchers and clinicians to classify the conditions in more detail and has led to huge improvements in the ability to give people a quicker and more precise diagnosis.

But just as importantly, understanding muscle function and the biological processes that can lead to muscle disease has given researchers the tools to develop ways to treat the diseases. leading the way forward

12 For many muscle and nerve conditions, promising technologies are currently being tested in clinical trial. Although this is not a guarantee that a treatment will soon be available, it is good news that pharmaceutical companies and other funding organisations believe that these technologies are so promising that they are prepared to invest the money to carry out the clinical studies. Below is a summary of some of these new developments.

You can find lots more information on these and many other trials for more conditions on our website in the Research news and Clinical trials sections.

The first gene known to cause a muscle-wasting condition was found in 1987. Researchers discovered that mutations in the dystrophin gene can cause Duchenne muscular dystrophy.

It comes as no surprise, therefore, that Duchenne muscular dystrophy is the condition for which potential treatments were first developed.

The most advanced and currently most promising development is a technology called exon skipping. It involves small pieces of DNA called “molecular patches�, which mask the portion of the dystrophin gene where there is a mutation and restores dystrophin production. Exon skipping is a personalised medicine – the molecular patch needs to be tailored to the specific mutation in the dystrophin gene.

Clinical trials have been carried out both by a group of British scientists, the MDEX consortium, in collaboration with the pharmaceutical company AVI Biopharma and by the Dutch company Prosensa in collaboration with GlaxoSmithKline (GSK). In order to gather evidence of how well this might work, both collaborative groups have been using a molecular patch to skip exon 51. If successful, this could be used to treat about 13 percent of boys with Duchenne muscular dystrophy. I am often asked whether both companies are testing the same thing: the answer is no. To deliver the molecular patches safely and efficiently to the muscles and the heart, they have to be linked to a chemical compound. And here lies the difference - the two companies are using different chemical compounds and at the moment we do not know which one will work best. www.muscular-dystrophy.org/research

13 The published results of the clinical trials completed so far show that both types of molecular patches are safe and result in the production of dystrophin. But both groups found that the amount of dystrophin produced seems to vary between different boys.

Prosensa/GSK are currently conducting a large international phase 3 clinical trial involving more than 200 boys to investigate how well the molecular patch improves muscle function.

The expected end date of this study is December 2012, but all boys that have participated will be entering into an extension trial lasting a further 48 months to study the long-term benefits.

Prosensa and GSK’s efforts, however, are not limited to exon 51. The companies have started a clinical trial to test molecular patches for exon 44 and have molecular patches for exons 45, 52, 53 and 55 in pre-clinical development.

These could be used potentially to treat a further 25 percent of boys.

A lot of effort has gone into developing this technology and it would be a great advantage if this could be used potentially to treat other conditions as well. And the good news is that researchers are already looking at using this technology in different ways to treat other diseases. Researchers have already carried out experiments in animal models of myotonic dystrophy (DM1). The results of these experiments have been promising and Prosensa/GSK are now developing this technology further to test how well it works in individuals with myotonic dystrophy.

For spinal muscular atrophy (SMA), results of recent experiments have also been positive, although they suggested that in animals there is only a short window of time after birth when the technology works best.

Isis Pharmaceuticals, a USA-based biotechnology company, started a phase 1 clinical trial at the beginning of this year to test the safety and tolerability of a molecular patch for children with SMA. The condition is caused by a mutation in a gene called ‘survival motor neuron 1’ (SMN1), which is crucial for the survival of motor neurons – the nerves that control muscle movement. No SMN protein is produced in individuals with SMA. Every person, however, has a second copy of the gene called SMN2, but the gene does not produce sufficient SMN leading the way forward

14 protein to compensate for the lack of SMN normally produced by SMN1. In the case of SMA, the molecular patch has been developed with the aim of increasing the levels of SMN protein produced from the SMN2 gene.

There are numerous other clinical trials testing a variety of drugs. The Oxford-based company, Summit Corporation plc, has announced the start of a phase 1 clinical trial to test a drug – SMT C1100 – to raise the levels of utrophin in boys with Duchenne muscular dystrophy. In animal models it was shown that utrophin can compensate for the lack of dystrophin, but only if produced at sufficiently high levels. A previous phase 1 study in healthy volunteers carried out by the pharmaceutical company Biomarin failed to show that the drug reached the muscles in high enough concentrations. Summit Corporation plc has since reformulated the drug into a form that should be better absorbed and it is hoped that this new formulation reaches the muscles at levels high enough to increase utrophin levels. Muscular Dystrophy Campaignfunded researcher, Professor Dame Kay Davies has been working for more than

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25 years to develop this potential treatment, which might also be used for boys with Becker muscular dystrophy.

In April, USA-based pharmaceutical company, Repligen, announced positive results from a phase 1 clinical trial of their drug RG3039. The drug had shown promise in a mouse model of SMA – the mice had an increased lifespan and symptoms typical to SMA were partially relieved. Different doses were tested in healthy volunteers and the study showed that all dose levels were well-tolerated with no serious side effects.

The Swiss-based company, Santhera pharmaceutical, has also announced the start of a phase 1 clinical trial. They hope to recruit participants in the second half of 2012 to test their drug Omigapil in patients with Ullrich congenital muscular dystrophy, Bethlem myopathy and merosin-deficient congenital muscular dystrophy (MDC1A).

In animal models, Omigapil was shown to reduce muscle cell death, protect muscle tissue and the muscles were healthier with less damage than was detected in the untreated animals. The clinical trial was made possible through collaboration with EndoStem, a Europe-wide consortium of clinicians, scientists, biotech and pharmaceutical companies. One of two centres where the trial will take place is Great Ormond Street Hospital, London, under the leadership of Professor Francesco Muntoni. The Muscular Dystrophy Campaign gave vital support for this trial by funding a clinical fellow and a clinical trial co-ordinator to develop the clinical trial protocol and to help with the huge administration a trial involves.

I hope I have given you some insight into the exciting developments that are currently underway here in the UK and in other countries. Hundreds of studies are currently being carried out to test new technologies not only to address the genetic mutations leading to the different forms of muscle disease, but also to help with the symptoms. In the coming years, we will gain a better understanding of how well these new treatments might work and whether the hopes of our families have been realised. With your help, the Muscular Dystrophy Campaign remains committed to investing in research until these treatments and cures are found.

15

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.

Our 14 year old son has Duchenne muscular dystrophy. The doctors have suggested using the supplement creatine based on a report by ‘The Cochrane Collaboration’ published in February 2011. Is there any recommended protocol or dosing regimen for the use of creatine?

Geoffrey and Fiona McMullen, Northern Ireland.

A.

Creatine is a naturally occurring substance in the body that helps to supply energy to muscle and nerve cells. We get approximately half of our creatine supply from food, especially meat and fish, and our liver and kidneys produce the rest. Athletes and body builders have used creatine supplements for decades to improve their performance.

The Cochrane Collaboration independently and systematically reviews research into human health care. In their review “Creatine for treating muscle disorders” they analysed the results of 14 randomised controlled trials of creatine treatment involving 364 participants with a wide variety of muscle conditions. They concluded that creatine treatment increased muscle strength in muscular dystrophies but not in metabolic myopathies (lipid and glycogen storage diseases and mitochondrial myopathies).

In the review, three trials of creatine for Duchenne muscular dystrophy

were included because they were considered of high enough quality.

One of the studies also included three Becker muscular dystrophy patients. In total 60 trial participants took creatine and 61 took a placebo. When the trials were considered separately some of the results were inconclusive but by pooling the results in the Cochrane review they found that there was about a nine percent improvement in muscle strength in the treatment group (for example by measuring hand grip strength).

The Cochrane review commented that long-term studies (greater than one year) are not currently available to assess the safety of creatine supplementation in people with muscle conditions. However, in studies up to six months in duration there did not appear to be any significant side effects. Creatine is sold as ‘creatine monohydrate’ in pharmacies and health food stores. The usual dose is four grams daily for adults (e.g. two grams twice daily) and two grams daily for children (e.g. one gram twice daily) dissolved in a glass of liquid. If taking creatine supplements you should make sure you drink plenty of liquid throughout the day. If you are taking any supplements, you should always mention this to your doctor.

Professor Volker Straub, Newcastle University, TREAT-NMD Project Coordinator.

Q.

If exon skipping becomes available as a treatment for Duchenne muscular dystrophy in the future, will it reverse the damage already done to the muscle? If not do you think anything could be done to help rebuild the damaged muscle?

Anonymous

A.

The muscle wasting in Duchenne muscular dystrophy is caused by break down of the muscle tissue. This causes inflammation and eventually the muscle is replaced with scar tissue.

Restoring dystrophin through exon skipping should stabilise the muscle and prevent further destruction and muscle wasting. This in turn will decrease inflammation - this has already been shown in the clinical trial conducted by AVI Biopharma which will prevent further scar tissue formation. Thus the progression of Duchenne muscular dystrophy should stop and we hope there will be an improvement in muscle function as a direct result of the presence of dystrophin. The body has the potential ability to remodel some of the scar tissue once inflammation has stopped so there should be some further improvement in function. However, it might not lead to the formation of new muscle fibres or reduce the amount of existing scar tissue.

Clinicians and researchers think that a combination of treatment approaches might be needed to significantly improve muscle function in Duchenne muscular dystrophy.

Once we understand how well exon skipping works to successfully halt the progression of Duchenne muscular dystrophy then we can look at ways to build up the remaining muscle. For example, researchers are currently working on finding ways to block myostatin (a protein that regulates muscle weight). It has been shown in animal models that this could increase the size of the remaining muscle. At present it is not clear whether we will be able to reverse the damage that has already been done to the muscle.

Professor Dominic Wells, Professor in Translational Medicine, Royal Veterinary College, University of London

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