Target Research 2014 (4 of 4)

Target Research Issue 4 of 4 2014

Million pound boost for neuromuscular research We announce our newly awarded projects

Our research impact

Find out more about our summer of events

New alliances established We launch new funding partnerships 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.

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. 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.

Molecular patch – a short piece of genetic material (DNA or RNA) which can bind to a specific gene and change how the code is read. Also called an antisense oligonucleotide.

Mouse model – see animal model.

Mutation – a permanent change in the DNA code that makes up a gene. Depending on where the mutation occurs, and the type of mutation, they can either have no effect or result in genetic diseases such as muscular dystrophy. Mutations can be passed on from generation to generation.

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

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

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

Phase 3 clinical trial – a 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.

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.

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

We are dedicated to beating muscular dystrophy and related neuromuscular conditions by finding treatments and cures and to improving the lives of everyone affected by them.

The Muscular Dystrophy Campaign’s medical research programme has an international reputation for excellence, investing more than £1m each year, which includes more than 25 live projects taking place at any one time.

Our information, care and support services, support networks and advocacy programmes support more than 5,000 families across the UK each year. We have awarded more than 6,000 grants totalling more than £6m towards specialist equipment, such as powered wheelchairs.

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

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

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

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Welcome

Welcome to the final edition of Target Research of 2014. In this edition we introduce the ten new research projects that were awarded this year. We will be investing over £1m over four years into the projects that cover nine conditions including spinal muscular atrophy and facioscapulohumeral muscular dystrophy. All the projects were selected using our rigorous peer review process to ensure that we continue to fund only world class research. Some of these projects have been co-funded by other charities, including a newly formed partnerships with The SMA Trust and CMT United Kingdom – you can find out more about this, and the Collagen VI alliance on page 9.

Our second article features the Research events that have been taking place over the summer. The events, in London and Edinburgh highlighted the impact of our research programme and gave our supporters the chance to go on a behindthe-scenes tour of a research laboratory and to talk to world-leading scientists and clinicians.

I do hope you enjoy this edition of Target Research.

Neil Bennett Editor, Target Research t: 020 7803 4813 e: research@muscular-dystrophy.org tw: twitter.com/ResearchMDC

Contents 4

Million pound boost for neuromuscular research We announce our newly awarded research projects

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New alliances established To tackle SMA and fund Collagen VI research

10 Research news

A round up of news stories from around the world 12 Research News and news in brief

The latest research news from around the world 13 Our research impact

Find out more about our summer of events 15 Making the most of exon skipping

Dr Marita Pohlschmidt, Director of Research Follow us on: www.facebook.com/musculardystrophycampaign Follow us on: www.twitter.com/TargetMD www.muscular-dystrophy.org/research

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Million pound boost for neuromuscular research

We are delighted to announce the investment of over one million pounds into a cuttingedge research programme, covering a number of conditions and potentially benefiting others, giving a dramatic boost to neuromuscular research.

Ten research projects, listed below, will be funded at a total cost of ÂŁ1,086,264 over four years, a sum that has been made possible thanks to the generosity of our supporters and collaborations with other research charities that are co-funding several of the projects. These include a newly founded partnership with The SMA Trust and CMT United

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Kingdom as well as our ongoing partnership with the Duchenne Forum, a funding partnership of UK charities that supports a programme of world-class research to find effective treatments and cures for Duchenne muscular dystrophy.

The newly awarded projects cover nine different conditions, demonstrating our commitment to actively tackling a broad range of muscle-wasting conditions through our research programme. Over the next four years, the researchers working on these ten projects will address important research questions that will investigate the underlying biological mechanisms of muscle condition and test the feasibility of new potential treatments.

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Exploring the views of men with Duchenne muscular dystrophy on end-of-life care decision making

Understanding muscle fibre death in Duchenne muscular dystrophy

Evidence suggests that talking about end-of-life care planning can be of help to people with life-limiting conditions. However, this is a highly sensitive topic that is often difficult for individuals, families and clinicians to discuss. Professor David Abbott from Bristol University will consult men with Duchenne muscular dystrophy to find out how, when and with whom they would like to have these conversations.

During the course of the project, 20 men with Duchenne muscular dystrophy from across the UK will be interviewed for their views and opinions about end-of-life care discussions. The DMD Pathfinders – an organisation for men with Duchenne muscular dystrophy – will help the researchers recruit participants aged over 20 years. The interviews themselves will be divided between Professor Abbott, who has worked with men with Duchenne muscular dystrophy before, and Dr Helen Prescott, a psychologist.

The results will be collated into a report with recommendations about how men with Duchenne muscular dystrophy would like end-of-life care discussions to take place. The report will be disseminated to clinicians and health and social care professionals and should improve clinical practice in this area. The report will also be relevant to family members and men with Duchenne muscular dystrophy and a summary will be available on the internet.

In this project, Professor Jenny Morgan and her team at University College, London will use a mouse model to investigate the biological process that leads to muscle fibre death in Duchenne muscular dystrophy. They will establish whether a newly identified process is a primary mechanism of cell death and if so, search for potential therapeutic targets that could prevent the loss of muscle fibres.

The lack of dystrophin in the muscles of boys with Duchenne muscular dystrophy eventually leads to muscle fibres being damaged and dying. Although muscle stem cells can repair this damage and replace lost muscle fibres, the stem cells are eventually exhausted and muscle damage continues.

The biological mechanisms that lead to the death of muscle fibres in Duchenne muscular dystrophy are not understood, but recent evidence has suggested that a newly discovered process of regulated cell death may play a role. This project will increase our understanding of the cellular process that leads to muscle fibre death in Duchenne muscular dystrophy. Specifically, the results will indicate whether regulated processes play a significant role in muscle fibre death and whether interfering with the pathways leading the cell to die could offer a useful therapeutic approach.

JOINT FUNDED WITH THE DUCHENNE FORUM

Grant information Project leader: Professor David Abbott Location: Bristol University Conditions: Duchenne muscular dystrophy Duration: one year Total project cost: £ 44,394 Official title: Building the Evidence Base for End of Life Decision Making for Men with Duchenne Muscular Dystrophy

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JOINT FUNDED WITH DUCHENNE CHILDREN’S TRUST AND DUCHENNE RESEARCH FUND

Grant information Project leader: Professor Jenny Morgan Location: University College, London Conditions: Duchenne muscular dystrophy Duration: three years Total project cost: £154,065 Official title: Mechanisms of myonecrosis in Duchenne Muscular Dystrophy: can we control the death of muscle fibres?

Developing a cell- and gene-based therapy for Duchenne muscular dystrophy JOINT FUNDED WITH DUCHENNE CHILDREN’S TRUST AND DUCHENNE RESEARCH FUND

Dr Tedesco and his PhD student will use a mouse model to test the feasibility of a novel cell therapy that could be used to restore dystrophin production in boys and men with Duchenne muscular dystrophy. The researchers will take skin cells from boys with the condition and genetically re-programme them to become a type of stem cell called induced pluripotent stem (iPS) cells, which can develop into any cell or tissue type, including muscle.

The mutated dystrophin gene in the iPS cells will be repaired by inserting a human artificial chromosome (HAC) containing a functional copy of the dystrophin gene and the cells will be grown in the laboratory and developed into a type of cell known to develop into muscle cells. These cells will be injected into mdx mice – an animal model of Duchenne muscular dystrophy – where researchers believe they will develop into healthy human muscle cells that will repair the muscle damage in the mouse model.

This will be an important step in the development of a potential approach using combined cell and gene therapy for Duchenne muscular dystrophy. However, this work is at an early stage – performing initial studies of effectiveness and safety in a mouse model – so it would be some time before it could be tested in clinical trials.

Grant information Project leader: Dr Saverio Tedesco Location: University College, London Conditions: Duchenne muscular dystrophy, Becker muscular dystrophy Duration: four years Total project cost: £114,326 Official title: Towards a genomic integration-free, iPS cell- and human artificial chromosome based therapy for Duchenne muscular dystrophy

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Protecting motor neurones in spinal muscular atrophy

Developing a genetic therapy for spinal muscular atrophy

Understanding the genetics of myotonic dystrophy type 1

Spinal muscular atrophy (SMA) is caused by deterioration of motor neurones (the nerves that connect the spinal cord to muscle), but certain populations of motor neurones escape this fate. Preliminary work from Professor Gillingwater’s group has shown that in protected motor neurones, certain genes are turned on or off, suggesting the activity of these genes plays a role in protection. In this project, the group aims to identify the specific genes and pathways involved in this protection, by measuring gene activity in different populations of motor neurones in mice with and without SMA. Genes that have different activities in protected motor neurones, could be promoting survival. These genes will be studied in a zebrafish model of SMA, which allows changes in gene activity to be made easily using genetic or pharmacological techniques.

Understanding why some motor neurones are protected in SMA, when others are lost, will provide fundamental biological insights into the mechanisms of SMA, and will also identify critical features of protected motor neurones that protect them from degeneration. This may highlight attractive therapeutic targets for ensuring ‘survival’ characteristics in all motor neurones in SMA; it may be possible to use pharmacological or genetic techniques to reproduce this protective effect in vulnerable motor neurones in people with SMA and related conditions.

Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene which lead to a lack of SMN protein – which is crucial for motor neurone survival. A second gene, called SMN2, also carries the information to produce SMN protein, but does not produce normal levels of SMN protein owing to a change in its genetic code. However, the effects of this change can be overcome using an adapted form of exon skipping technology to alter the way the SMN2 genetic code is read.

One challenge for this potential therapy is delivery; to maximise the therapeutic effect, the molecular patches need to access the brain and spinal cord. Injecting the molecular patches directly into the spinal cord overcomes this limitation, but this is an invasive procedure.

Professor Wood and his team have been developing and testing short protein fragments called peptides that can be linked to the molecular patches and allow them to reach the brain and spinal cord without the need for spinal cord injections.

In this project, the researchers will identify the one most efficient at delivering molecular patches to the central nervous system of a mouse model of SMA and establish the dose required. This work, if successful, will lead to further preclinical development work on the peptide-linked molecular patches which would be a necessary step before pursuing clinical trials.

Myotonic dystrophy type 1 is caused by a mutation called a ‘triplet repeat expansion’ in the DMPK gene.

Individuals are affected when the number of repeats within the gene is increased beyond the range usually observed in the general population.

The severity of the condition is at least partly due to the number of repeats; a larger number is associated with more severe symptoms and an earlier age of onset.

In this project, Professor Monckton and his team at Glasgow University will investigate in detail how the complex and changeable mutations that cause the condition may be linked to the extreme variability in the severity of the symptoms people experience.

Understanding this link will help clinicians to provide information on the progression of the condition to people affected. This means individuals will know what to expect in the future, which can help them and their families to prepare in advance and to plan their lives around these expectations.

The study findings will also be useful in choosing participants for, and interpreting data from future clinical trials, where different mutations may affect the potential effectiveness of a trial treatment. This is something that would otherwise be very difficult for such a variable condition.

Understanding why some individuals have unexpectedly mild symptoms may also provide new insights into potential therapies.

Grant information Project leader: Professor Tom Gillingwater Location: Edinburgh University Conditions: Spinal muscular atrophy Duration: two years Total project cost: £118,000 Official title: Identifying and protecting vulnerable motor neurones in spinal muscular atrophy (SMA)

Grant information Project leader: Professor Matthew Wood Location: Oxford University Conditions: spinal muscular atrophy Duration: three years Total project cost: £82,173 Official title: Central nervous system delivery peptides conjugated to oligonucleotides for splice switching therapy of spinal muscular atrophy

JOINT FUNDED WITH THE SMA TRUST

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JOINT FUNDED WITH THE SMA TRUST

Grant information Project leader: Professor Darren Monckton Location: Glasgow University Conditions: myotonic dystrophy type 1 Duration: three years Total project cost: £177,530 Official title: Cis and trans-acting genetic modifiers of myotonic dystrophy type 1

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Generating a model of FSH and testing a potential therapeutic approach Facioscapulohumeral muscular dystrophy (FSH) is most often caused by the deletion of a segment of DNA in a region called D4Z4. D4Z4 consists of a number of repeated units of DNA and in people with FSH, the number of repeats in the D4Z4 region is less than in unaffected individuals. The deletion leads to the abnormal production of a protein called DUX4 from the last D4Z4 unit, that is toxic to muscle cells.

However, the biological pathways that lead to the production of DUX4 and the molecular effects that cause the muscle cell death are not well understood.

Professor Zammit aims to address some of these questions by generating a mouse model that will allow an analysis of the genetic switch that turns DUX4 protein production on and off in cells. Initially, the researchers will use the mouse model to investigate how, when, and in which cells DUX4 protein production is turned on. A better understanding of the biological pathways that lead to the production of DUX4 protein could help to identify targets for future therapeutics.

The mouse model the group develops will also be used to test a potential therapeutic approach that could prevent DUX4 protein being produced by the last D4Z4 unit. The researchers will test whether short pieces of genetic material called molecular patches are able to prevent protein production and explore the feasibility of developing this into a future therapeutic approach for people with the condition.

Grant information Project leader: Professor Peter Zammit Location: King’s College, London Conditions: facioscapulohumeral muscular dystrophy Duration: three years Total project cost: £174,271 Official title: Modeling FSHD as a platform for testing therapeutics

www.muscular-dystrophy.org/research

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Identifying biomarkers for congenital and limb girdle muscular dystrophies Biomarkers are molecules that can be easily measured in a non-invasive way and whose levels change in line with the severity or progression of a condition. They can be used to monitor a condition and to measure the effectiveness of a potential treatment in clinical trials. There is a need to find such biomarkers for congenital and limb girdle muscular dystrophies.

Recent research has identified microRNAs, small pieces of RNA that regulate gene activity, as potential biomarkers for muscular dystrophies.

In this project, Professor Muntoni and his team will search for microRNAs that could be used as potential biomarkers in muscular dystrophies known as “dystroglycanopathies” which are caused by a lack of functional alphadystroglycan protein. This protein is essential for maintaining muscle cell structure and function. Several enzymes are required to produce alpha-dystroglycan protein, and mutations in one of several genes that carry the genetic blueprints for these enzymes can reduce the amount of functional protein. This can cause severe congenital muscular dystrophy; moderate Duchenne-like limb girdle muscular dystrophy, or mild limb girdle muscular dystrophies such as LGMD2I.

By analysing samples from people with conditions of different severities, Professor Muntoni hopes to identify microRNAs whose levels are affected by the severity of the condition and which could be used as potential biomarkers.

Grant information Project leader: Professor Francesco Muntoni Location: University College, London Conditions: congenital muscular dystrophy, limb girdle muscular dystrophy Duration: two years Total project cost: £27,493 Official title: Expression analysis of miRNAs in dystroglycanopathies and LAMA2-deficient Congenital Muscular Dystrophy

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Understanding cell membrane changes in centronuclear myopathy and Charcot-Marie-Tooth disease

CO-FUNDED WITH CMT UNITED KINGDOM

Some types of centronuclear myopathy and Charcot-Marie-Tooth disease (CMT) can be caused by mutations in a gene that carries the genetic blueprint for a protein called dynamin 2. This protein plays a role in an essential cellular process called endocytosis. Cells use this process to collect nutrients and messenger molecules from their surroundings and to maintain the structure of the membrane that encloses them.

Dr Shevchuk and his team have developed a new technique called scanning ion conductance microscopy which allows them to observe endocytosis in living cells. In this project, the researchers will use this technique to learn more about the effects that mutations in the dynamin 2 gene have on endocytosis.

They will study endocytosis in great detail in skin cells from people with centronuclear myopathy or CMT and compare them to cells from unaffected individuals. This will indicate precisely how the mutations disrupt endocytosis and at what stage of endocytosis the disruption occurs.

This project will increase our understanding of the molecular mechanisms underlying these conditions and will be useful for future drug development work it may help identify new therapeutics targets for future interventions.

Grant information Project leader: Dr Andrew Shevchuk Location: Imperial College, London Conditions: Charcot-Marie-Tooth disease, centronuclear myopathy Duration: three years Total project cost: £77,628 Official title: Centronuclear myopathy and Charcot-Marie-Tooth peripheral neuropathy -induced abnormalities in cell membrane transport

Developing a therapeutic approach for collagen VI-related muscular dystrophy Ullrich muscular dystrophy is caused by a lack of collagen VI protein, which acts as a scaffold to hold and support muscle cells. Some mutations in the genes that carry the blueprint for collagen VI protein have no effect on the amount of protein that is produced, but stop the scaffold assembling correctly. These mutations are inherited in a dominant way; a single copy of a mutated gene is enough to cause the condition.

Studies have shown that one functional copy of the gene is able to produce sufficient collagen VI protein to build an effective scaffold. Professor Muntoni aims to develop techniques to switch off or ‘silence’ a gene with a dominant mutation, to allow the second, healthy copy of the gene, to function normally.

In this project, two methods of ‘silencing’ the gene will be tested in cells grown in the laboratory: exon skipping and a new technique called RNA interference. Both use small molecules called oligonucleotides to prevent the mutated copy of the gene producing protein and have shown potential as a therapy for other conditions.

If successful, this project will prove the concept that oligonucleotides could be used therapeutically for Ullrich muscular dystrophy caused by dominant mutations.

The next steps would be testing in an animal model to investigate the safety and effectiveness of this potential approach.

Grant information Project leader: Professor Francesco Muntoni Location: University College, London Conditions: congenital muscular dystrophy, Ullrich muscular dystrophy Duration: two years Total project cost: £116,384 Official title: Allele-selective suppression by antisense oligonucleotide as a therapeutic strategy for collagen VI-related congenital muscular dystrophy

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Forming new partnerships In our last issue, we highlighted some of the partnerships we have formed with other charities and organisations. As well as continuing to work with these groups, we can now announce the formation of three new partnerships – an international alliance to fund research into conditions caused by a lack of collagen VI protein; and collaborations with The SMA Trust and CMT United Kingdom to co-fund our new projects focusing on spinal muscular atrophy and Charcot-Marie-Tooth disease (CMT).

The Muscular Dystrophy Campaign is delighted to announce that we will be working together with The SMA Trust to co-fund two newly-awarded research projects into spinal muscular atrophy in Professor Thomas Gillingwater’s and Professor Matthew Wood’s laboratories. You can find out more about these projects on page six.

We will also be collaborating with CMT United Kingdom to co-fund the project on CMT in Dr Andrew Shevchuk’s laboratory at Imperial College, London (see page eight).

Collaborations between the charities will accelerate progress in the search for effective treatments and eventually cures for muscle-wasting conditions.

“The two partnerships between the Muscular Dystrophy Campaign and The SMA Trust and CMT United Kingdom are great examples of charities working together effectively. By funding these projects together we can move promising therapies forward with greater speed, avoid duplication and keep costs to a minimum. The alliances are a really positive step forward in charitable funding for research into musclewasting conditions, and should be encouraging news for the thousands of families who loyally support our charities in the hope of beating these conditions.”

Robert Meadowcroft, Chief Executive at the Muscular Dystrophy Campaign

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Collagen VI Alliance calls for project applications A new international alliance has been established by AFMTéléthon, the Muscular Dystrophy Campaign, Muscular Dystrophy Ireland, Cure CMD and the Swiss Foundation for Research on Muscle Diseases to fund research into collagen VI deficiencies that will further the development of therapeutic approaches and/or demonstrate a strong translational research impact in this field.

In recent years great progress has been made in the development of treatments for a number of muscular dystrophies and related neuromuscular conditions and as a result the number of clinical trials is steadily growing.

Collagen VI deficiencies form a group of conditions designated as ultra-rare. However, investment into research for these conditions seems to lag behind other areas even if in some countries the prevalence is relatively high.

In order to drive the development of treatments for these conditions forward, AFM-Téléthon and the Muscular Dystrophy Campaign have joined forces in launching a Call for Projects dedicated to collagen VI deficiencies with a particular focus on Ullrich muscular dystrophy and Bethlem myopathy. The call is aimed at funding research that has a focus on developing therapeutic approaches and/or can demonstrate a strong translational aspect.

The research will be funded by the members of the Collagen VI Alliance and the call will be co-ordinated by the Muscular Dystrophy Campaign using our rigorous peer review process.

News 10

Research

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

Researchers demonstrate potential of genome surgery

Researchers in Dallas in the USA have published a study demonstrating the potential of a technique called genome surgery to repair mutations in genes inside a cell. The technique is based on an enzyme that functions like a pair of molecular scissors to cut DNA in a very specific place. The researchers used an enzyme that cuts the DNA of the dystrophin gene precisely at the location of the mutation in mdx mice (an animal model of Duchenne muscular dystrophy). The separated DNA was then repaired by cellular machinery using a DNA template which the researchers added to the cells, which contained the DNA sequence but with no mutation.

The technique was tested in embryos from mdx mice which were then implanted back into the mice. This produced offspring where some of the muscle fibres produced dystrophin protein. Researchers found that production of dystrophin in just 17 percent of cells could slow the decline in muscle function.

Although the study has shown that the technique is able to repair mutations inside cells, it would not be used this way in the clinic since pre-implantation genetic diagnosis can already be used to identify embryos with a functional copy of a gene.

To be used to treat people with a muscular dystrophy or related neuromuscular condition, the molecular scissors and DNA template would need to be delivered to the muscle cells. Researchers believe that Adeno-associated viruses (which cause few or no symptoms in humans) may be able to deliver the components to the muscles where they are required.

Genome surgery might also address a key challenge of developing stem cell therapies. In an individual with a genetic condition, each cell in the body carries the mutation that causes the condition. Approaches to develop an efficient stem cell therapy are therefore often based on the use of stem cells from a healthy donor. In this case the individual receives drugs to suppress the immune system which would otherwise recognise the donor cells as foreign and destroy them.

The use of an individual’s own cells represents a potentially more efficient approach to stem cell therapy, but this requires the repair of the genetic defect in the individual’s stem cells. Genome surgery offers a possible route for achieving this and the results of this research are an important step in providing the first proof-of-principle of a promising technology that would allow the gene’s function to be restored.

www.muscular-dystrophy.org/research

Prosensa and GSK publish drisapersen trial results Prosensa and GlaxoSmithKline (GSK) have published the full results of a phase 2 trial of drisapersen – a molecular patch that promotes skipping of exon 51 of the dystrophin gene. The paper demonstrates that after 25 weeks of treatment, boys receiving drisapersen every week were able to walk further in a six-minute walk test than those who received a placebo (an inactive form of the drug) or intermittent treatment with drisapersen.

Although the trial was most focused on the results after 25 weeks, participants received treatment for a total of 49 weeks. After this time, the data suggested that boys treated with drisapersen each week were still able to walk further in a six-minute walk test than those who received placebo. However, because the effects of Duchenne muscular dystrophy can vary widely between individuals, it is important for researchers to use statistical tests to ensure that the differences they measure are a result of treatment and not natural variation.

After 49 weeks, the statistical tests could not confirm that drisapersen caused the difference in the distance boys walked during the six-minute walk test.

Publication of the full results of the study is an important step. It gives researchers around the world access to data that could improve understanding of exon skipping and help in the design of future trials.

It must be noted that since the phase 2 study ended, Prosensa and GSK have tested drisapersen in a much larger phase 3 trial. Although preliminary results of that trial failed to show that the drug was effective, following a lengthy analysis of the results, Prosensa now believes that the drug may be effective in some individuals and the company plans to apply for a licence in the USA.

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Research investigates muscle damage and pain in Charcot-Marie-Tooth disease

An international team of researchers including Muscular Dystrophy Campaign-funded Professor Mary Reilly has published two studies investigating the type of damage that occurs in the muscles of people with Charcot-Marie-Tooth disease (CMT) and what causes the pain experienced by some people with the condition.

Despite previous studies, it is not clear what causes muscle damage in CMT. Now, researchers investigated whether exercise may be responsible – something called overwork. People who are right-handed typically use the muscles on their right-hand side (called their dominant side) more than those on the left.

By comparing the strength of muscles on the dominant and non-dominant sides of 271 people with CMT, the researchers could examine whether extra activity (or exercise) caused the muscles to weaken over time - as would be expected if exercise was causing muscle damage. When the strength of hand grip and leg muscles was compared in these individuals, researchers could find no evidence that increased activity led to reduced muscle strength, suggesting that muscle damage in CMT disease is not caused by overwork.

Karyomapping: researchers develop a new pre-implantation genetic test Researchers and clinicians in London have developed a new test that can be used for pre-implantation genetic diagnosis.

Using a new IVF-based technique called karyomapping allowed clinicians to select embryos not affected by a condition before implanting them into the womb of a mother at risk of having a child with a genetic condition. The first person in Europe to conceive after using this technique has Charcot-Marie-Tooth disease.

The news that the first person in Europe is now pregnant following use of a new IVF-based technique called karyomapping will be exciting news for many families affected by a muscular dystrophy or related neuromuscular condition.

Carmen Meagu has Charcot-Marie-Tooth disease and was told that she had a 50 percent chance of passing the condition to her children. Clinicians at the Centre for Reproductive and Genetic Health in London used the new IVF-based technique to identify unaffected embryos before they were implanted into the womb, and Carmen is now 17 weeks pregnant.

The new technique relies on the fact that the DNA of any

www.muscular-dystrophy.org/research

However, the researchers went on to say that they could not rule out that strenuous exercise could cause muscle damage and they concluded that individuals affected by CMT should be encouraged to exercise gently (or aerobically).

Understanding how exercise affects the muscles in people with a muscular dystrophy or related neuromuscular condition could help researchers and clinicians to learn more about how muscles work and how they are affected by these conditions.

Importantly, information generated in studies like this can also help clinicians to give information to their patients about whether they should exercise, how much they should exercise and what sort of exercises they should do.

In a second study, researchers investigated the cause of the pain experienced by some individuals with CMT. Pain was experienced by 43 of 49 individuals with CMT type 1A who took part in the study, and although it is a common symptom of the condition, its causes are not well understood. By using a number of different ways of assessing pain, researchers identified that while a small number of participants in the study experienced neuropathic pain (pain caused by problems in the nerve cells), most people experienced pain that was “multi-factorial in origin” – suggesting that a combination of causes such as altered gait and foot deformities may play a role.

A better understanding of the pain experienced by people with CMT will allow clinicians to identify the cause of the pain in affected individuals. This will enable clinicians and their patients to better manage the symptom, and could improve quality of life for those affected.

two individuals varies – often tiny changes where a single letter is used instead of another. These changes are specific to an individual, and if DNA from different members of the same family is analysed, researchers can build a family tree identifying which copy of a chromosome is inherited from which parent and even grandparent. In families affected by a genetic condition, comparing the inheritance of chromosomes to a family history of the condition can identify the copy (or copies) of the chromosome carrying a mutated gene that causes the condition.

Using the new technique, clinicians can take a single cell from an embryo (fertilised using IVF) and identify which chromosome was inherited from each parent and whether the chromosome carries the mutated or functional copy of the gene causing the condition. This allows clinicians to choose embryos that are not affected to be implanted into the mother’s womb.

The same karyomapping technique can be used for any genetic condition. The researchers believe that this will be more efficient than traditional pre-implantation genetic diagnosis which relies on testing embryos for the presence of a specific mutation found in one or both of the parents. However, like current PGD tests, karyomapping will only be useful when the gene causing an individual’s condition is known.

Importantly, clinicians hope that the new test will be available for people on the NHS and, like current PGD tests, will give carriers or individuals affected by genetic conditions the chance to choose to have an unaffected child.

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Research news

in brief

Mitochondrial transfer IVF update

As we have reported previously in Target Research, IVF-based techniques that have the potential to prevent the transmission of mitochondrial diseases from affected women to their children have been developed by Muscular Dystrophy Campaignfunded Professor Doug Turnbull at Newcastle University.

For the techniques to be tested further and moved forward into clinical trials, a change to the current regulations is required. This change would allow further laboratory research to be performed and eventually for an embryo to be placed into a woman’s womb in a clinical trial. The new draft regulations are currently being prepared and we hope the Government will present them to Parliament as soon as possible.

At the same time, the Human Fertilisation and Embryology Authority has performed a review of the current scientific position in the development of the techniques. The review paid particular attention to ongoing work using animal models to investigate the safety of the techniques and is an important step in moving the techniques towards clinical trials. Although it identified several key experiments which should be completed before the techniques are tested in people, encouragingly, the review found no evidence that the techniques are unsafe.

Skip-NMD project update

Members of the SKIP-NMD consortium met in Rome in the Summer for their latest scheduled six monthly meeting. The meeting was hosted by Professor Mercuri, one of the principal investigators of the project, and was attended by more than 30 members of the consortium which includes clinicians, scientists, radiologists and physicists, coordinators, therapists, ethicists, representatives from patient organisations from the UK, France and Italy and the consortium’s industrial partner Sarepta Therapeutics from the USA. The SKIP-NMD research project started in November 2012 with the award of an EU grant. The project brought together a consortium of researchers, clinicians and companies from across the field to develop and test a new molecular patch to skip exon 53 of the dystrophin gene. Skipping exon 53 could restore dystrophin production in individuals with mutations in exon 52 and mutations spanning exons 52, 45-52, 47-52, 48-52, 49-52 and 50-52.

To update families on the progress of the SKIP-NMD project and to provide information about the forthcoming SKIP-NMD clinical trial and clinical trials in general, the Muscular Dystrophy Campaign hosted a webinar in September. If you would like to watch the webinar, it is available on our website at www.muscular-dystrophy.org/ skipNMD.

Hello from Target MD In this edition of Target MD, we focus on our work in various parts of England.

Having been involved for some years with the Newcastle Muscle Centre, we bring you news of all we do there to fund research and improve the lives of people affected by musclewasting conditions. Not to mention a fun fundraising event the team there ran in August, to support our Move a Mile for Muscles initiative.

We also acknowledge the role of one of our Honorary Life Presidents, Lord Walton of Detchant, whose contribution over almost six decades to neuromuscular research in general and the work at the Newcastle Muscle Centre in particular has been extraordinary.

With stories of a fundraising grandmother, a cheeky chappy from Essex and his gift fit for a prince, as well old, young and new fundraisers and campaigners doing outstanding work, we trust this edition will entertain and inspire you.

With Christmas looming large on the horizon, please come and join us at a festive and magnificent Spirit of Christmas concert taking place near you, or don your Santa suit and join us in a local Santa run in December. Our online shop has a range of Christmas cards and gifts to choose from, so do browse around at www.musculardystrophy.org/shop From all at Target MD, I’d like to wish you a happy Christmas and every good wish for you and your families for 2015.

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

www.muscular-dystrophy.org/research

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Bringing families and researchers together This year we launched a series of events to update our supporters on the progress and impact of our programme of groundbreaking research. The events brought together researchers and families, giving our supporters the chance to meet some of the leading scientists in person and to chat informally over coffee and lunch. This gave researchers an opportunity to answer any questions our supporters had about the projects we are funding and about research in general.

The first research event was hosted

by Professor George Dickson at Royal Holloway (University of London) and was attended by more than 50 people with an interest in either Duchenne or Becker muscular dystrophy. The event gave our supporters the opportunity to hear more about our exciting research programme into these conditions.

The day featured talks from several of the researchers we support and a wide range of topics was covered. Dr www.muscular-dystrophy.org/research

Graham Wynn from Oxford University highlighted the challenges of developing drugs that could increase levels of utrophin; a protein that may be able to compensate for the lack of dystrophin protein that causes Duchenne and Becker muscular dystrophy. Professor Dickson showed the promising results of preclinical testing of using gene therapy approaches to deliver a functional copy of the dystrophin gene. Professor Steve Winder from Sheffield University highlighted how his recent work has investigated whether drugs used as cancer treatments could be adapted to treat Duchenne muscular dystrophy.

Dr Valeria Ricotti from Great Ormond Street Hospital focused on the importance of natural history data, and how data collected by the Muscular Dystrophy Campaign-funded NorthStar database was used to demonstrate for the first time the effectiveness of steroid treatment in helping boys and young men with Duchenne muscular dystrophy to walk for longer.

The day ended with a clinical trials update from Professor Nic Wells from the Royal Veterinary College. This included the news of the conditional approval of Translarna (a drug that may treat the underlying genetic cause of

Duchenne muscular dystrophy caused by nonsense mutations), and the ongoing trials of exon skipping, as well as potential therapies that aim to treat various symptoms of Duchenne and Becker muscular dystrophy.

“Funding for research and clinical trials from medical charities has been and continues to be vital in advancing our work and the hard work and dedication of the Muscular Dystrophy Campaign and other patient and family organisations is incredibly important and very much appreciated.”

Professor George Dickson “It’s really exciting to hear about the research taking place at Royal Holloway University and how far things have come along just in the past five years.

“We left the laboratory tour feeling that now, more than ever, we must raise more money to help Professor Dickson and his colleagues with their work.”

Sue Barnley, whose son Harry has Duchenne muscular dystrophy In September, our second event took place at Edinburgh University in Scotland. The day was hosted by Muscular Dystrophy

14 Campaign-funded Professor Thomas Gillingwater, whose work focuses on understanding the role of certain types of cell in the development of spinal muscular atrophy. SMA is caused when the absence of a protein vital for nerve cell survival leads to the death of motor neurones.

Professor Gillingwater highlighted how other types of cells may play a role in the development condition and how his laboratory is using of the animal models to understand precisely what is happening.

“We are very grateful to the Muscular Dystrophy Campaign for funding our research and we are delighted to be able to show some of the people who have worked so hard to raise this money around the laboratory.”

Professor Gillingwater

I found the event very “helpful and interesting; thank you to everyone involved. “ John Veene, whose daughter has congenital muscular dystrophy

We were joined by Dr Sarah Cumming from Professor Darren Monckton’s laboratory at Glasgow University. She explained her work on the complex genetic cause of myotonic dystrophy.

Understanding this may be crucial for selecting participants in future clinical trials for the condition. Dr Lizzie Harris from Newcastle University highlighted the benefits of using next generation sequencing – a technique that allows the DNA code in all of an individual’s genes to be read at once – to find mutations that cause limb girdle muscular dystrophy. This has helped Dr Harris to provide a genetic diagnosis to more individuals.

Finally, Dr Angela Russell from Oxford University showed our supporters the exciting results of her work to develop new molecules with the potential to increase levels of utrophin as a potential treatment for Duchenne muscular dystrophy.

Our supporters also got the chance to don a lab coat and take a behindthe-scenes tour around a research laboratory. Microscopes were used to study cells growing in tissue culture and the visitors even got to try their hand at pipetting!

Our final event of the summer was held at the Institute of Child Health in London. A small group of www.muscular-dystrophy.org/research

Looking around a research “laboratory was a wonderful

experience, although I wasn’t expecting to have to do things!

Talking to the scientists, and seeing the work that goes on in a laboratory has really shown me how much effort and learning goes into the research we are funding.

“

families affected by merosin-deficient congenital muscular dystrophy and Ullrich congenital muscular dystrophy were welcomed by Professor Francesco Muntoni.

We were joined by Professor Carsten Bönnemann who made the long journey from the USA to attend the meeting and update families on his research. Professor Bönnemann is the principal investigator in one of the first clinical trials for Ullrich congenital muscular dystrophy. The trial will investigate how omigapil (a drug that may slow muscle fibre death) is absorbed and metabolised in children with Ullrich or merosin-deficient congenital muscular dystrophy.

Dr Regan Foley, a former Muscular Dystrophy Campaign-funded Clinical Training and Research Fellow also travelled to London from the USA for the event. She highlighted the importance of our Clinical Fellowship programme that supported her work to develop methods to monitor the progression of congenital muscular dystrophies and for testing the effectiveness of potential treatments in future trials.

The programme also included workshops from Marion Main, a physiotherapist at Great Ormond Street Hospital, and from the Muscular Dystrophy Campaign Trailblazers team. The afternoon also featured an extensive Question & Answer session where presenters were put on the spot by families’ questions about research, clinical trials and care.

“I found the event very helpful and interesting; thank you to everyone involved. It was brilliant to hear the latest news about the trial of omigapil that is taking place in the states as well as the exciting research that is taking place around the world.”

John Veene, whose daughter has congenital muscular dystrophy

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Making the most of exon skipping As you probably have already read on previous pages, the charity made massive investments this year into 10 new outstanding research projects.

I am particularly pleased that the projects revolve around a staggering nine conditions. And the other extremely encouraging news is that long-term investments seem to pay off.

Those who follow news updates about clinical trials into Duchenne muscular dystrophy might know that exon skipping is one of the technologies regarded as particularly promising.

While there is still a lot to do until we fully understand how well exon skipping really works, the results so far are encouraging. In one study initiated

by Sarepta Therapeutics in the US, boys seemed to be stable for approximately two years in their walking ability when treated with eteplirsen.

The charity played a crucial part in this success and we have supported research into exon skipping for more than 20 years. Hence we are particularly delighted that in some of the new projects this technology will be tested as a potential treatment for three other conditions and I am certain that those affected will not have to wait for another 20 years to find out whether this will work for them.

So let’s make the most of exon skipping and with your support and commitment we can do it.

Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign

www.muscular-dystrophy.org/research