Target Research 2013 (3 of 4)

Target Research Issue 3 of 4 2013

Laboratory visits Our supporters go behind the scenes

Gene Therapy Using viruses to deliver genes

Register Now! Join the newly launched FSH registry

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

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About us

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.

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

Adeno-associated viruses (AAV) – a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. These features make AAV a very attractive vehicle for delivering gene therapy into cells.

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.

Animal (mouse) 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.

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

Molecular patch – a short piece of genetic material (DNA or RNA) which can bind to a specific gene and change how the code is read. They can be used to mask errors in the genetic code, this is known as exon skipping and is in clinical trial for Duchenne muscular dystrophy. Certain types are also being investigated in the laboratory for their ability to completely switch off genes. Also called antisense oligonucleotides.

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.

Mutation – the alteration of a gene. Mutations can be passed on from generation to generation.

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.

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.

Dystrophin – the protein missing in people who have Duchenne muscular dystrophy and reduced in those who have Becker muscular dystrophy. The dystrophin protein normally sits in the membrane that surrounds muscle fibres like a skin, and protects the membrane from damage during muscle contraction. Without dystrophin the muscle fibre membranes become damaged and eventually the muscle fibres die.

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

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

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

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

Non-sense mutation – a change in the DNA which causes a premature stop signal to occur in a gene.

When this happens protein is either not produced at all or does not function properly.

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

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

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.

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.

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’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 new address 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

www.muscular-dystrophy.org/research

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Welcome On the cover A computer generated image of a virus which researchers hope could be used to deliver gene therapies. See page 4 for more details.

In this issue, we take a closer look at the development of gene therapies – which may offer the potential to treat the genetic mutation which underlies a condition.

Researchers hope to use harmless viruses to deliver a healthy copy of a gene to the cells where it is needed. This could restore production of a missing protein, and might have the potential to treat some of the conditions we cover.

We also talk about visits to our researchers at Oxford University and Royal Holloway (University of London) which were enjoyed by some of our families from around the country.

Cover photo: adventrr/istock

Before I close this column, I’d like to highlight one change, and that is our new twitter account. For all the latest updates, follow @researchMDC. I do hope you enjoy this issue of Target Research. If you have any feedback or there are any research questions you’d like us to answer in the next issue, I’d love to hear from you.

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

Contents 4

Gene therapy: how viruses could be used to deliver genetic treatments

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Research News: the latest news from the UK and around the world

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Twigs in a bundle are unbreakable Dr Marita Pohlschmidt, Director of Research

10 Behind the scenes:

our supporters visit our researchers in Oxford and London

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

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Gene therapy Many rare diseases, including muscular dystrophies and related neuromuscular conditions, are inherited and are caused by a mutation in a gene vital for the function of a cell. Gene therapy aims to deliver a healthy copy of the mutated gene to the affected cells which could be used to produce the missing protein.

Since 1990, the potential of the technology has led to billions of pounds being invested in gene therapy research all over the world. This huge investment helped scientists to develop new cutting edge technology and now, some of this technology is being tested in clinical trials.

In this article we focus on how viruses are being developed and tested to deliver a healthy copy of a gene in people with a muscular dystrophy or related neuromuscular condition.

How does gene therapy work?

Genes carry the information needed by our cells to produce the proteins our body needs to function properly. In the laboratory, researchers can manipulate DNA to produce an artificial gene that carries the genetic blueprint for a certain protein that can then be used to develop gene therapy approaches.

If an artificial gene was injected into a human or animal as naked DNA, the gene would be destroyed by our body’s defences before it could reach its intended target and the protein would never be produced. The gene must therefore be carried and delivered by something which can protect it from destruction.

In this way, gene therapy can be thought of as sending a greetings card. A card aims to send a message (a gene) to a distant place (a muscle, for example). If we just put a greetings card in the post box, it will never arrive. There is no envelope to protect it, or address to tell the postman where to deliver it.

It has taken researchers many years to develop biological envelopes to carry genes into tissues, and to find ways to address them. With the right envelope and address, a gene can be sent to the cells where it is most needed. The most common “envelopes� being tested today are viruses, and in this article we explain how they are used and update you on the research and clinical trials being undertaken to develop and test new potential gene therapies. www.muscular-dystrophy.org/research

BUT WHAT ABOUT OUR IMMUNE SYSTEM? Our immune system is designed to protect us from infections, including those caused by bacteria and viruses.

Since our immune system cannot tell the difference between a virus that is potentially harmful and one being used for therapy, the therapeutic viruses can trigger an immune response. Adeno-associated virus causes weak immune responses but even this could destroy the virus and the infected cells, and render the treatment ineffective. Immune responses can also cause side effects and prevent repeat doses of a gene therapy being given. Developing techniques to stop, or suppress the immune system is therefore important for gene therapy to work.

There are several strategies currently being developed. Various regimes of drugs to suppress the immune system while the patient undergoes treatment are being tested. Secondly, the route of administration is very important in influencing immune responses.

Injection directly into the muscle is not ideal because high local concentrations of the virus in the muscle are more likely to trigger an immune response. It is hoped that administration into the bloodstream will dilute the introduced virus and cause milder immune reactions.

Photo: adventrr/istock

DELIVERING NEW GENES

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Using viruses to deliver a gene?

Viruses were chosen for the development of gene therapy approaches because they are naturally adept at delivering genes. When viruses infect a cell, they hijack the cell’s biological machinery to read their own genes to make the proteins needed to produce more viruses. By replacing some of the virus genes with an artificial gene designed for therapy, researchers can use a virus to carry a gene into cells and make the protein. At the same time, removing some of the virus’ genes prevents virus growth and stops it spreading uncontrollably around the body.

Many types of virus have been investigated for their suitability for use as biological envelopes. Currently, the most widely used is called Adeno-associated virus. This virus was chosen for a number of reasons: it is known to infect human cells but it is not known to cause severe disease; it is able to infect a wide range of tissues including the muscles, brain and heart; and importantly, genes delivered by an Adeno-associated virus are kept separate from the cell’s own genes. This minimises the risk of disrupting important cellular genes, such as those which prevent cancer. The first evidence that Adeno-associated viruses could be used to deliver a gene to cells came in 1984. By the early 1990s, scientists believed Adeno-associated viruses could be used to treat genetic diseases and in the mid-1990s the first clinical trials started. But it wasn’t until the end of 2012 that the first gene therapy – called Glybera – received approval in Europe.

Glybera is a gene therapy for a condition called lipoprotein lipase deficiency.

This is a rare inherited condition caused by mutations in the gene carrying the blueprint for a protein called lipoprotein lipase. In healthy individuals, lipoprotein lipase plays an important role in dealing with the fats from the food that we eat.

When the protein doesn’t work properly, or there is not enough of it, fat levels in the blood can increase dramatically. Glybera delivers a healthy copy of the lipoprotein lipase gene to the muscle. Muscle cells are the most important source of lipoprotein lipase, and by using an Adeno-associated virus that preferentially infects muscle cells, the healthy copy of the gene can be delivered to the place it is most required.

While lipoprotein lipase deficiency is not a muscle-wasting condition, the approval of glybera is exciting news for researchers developing gene therapies for other conditions. Having a gene therapy on the market which delivers a functional gene to muscles will demonstrate that the techniques can work and will encourage the scientific community to develop gene therapies for neuromuscular conditions.

Using viruses for gene delivery Gene for therapy Adeno-associated virus

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4 3 Cell nucleus 1. Some of the Adeno-associated virus genes are replaced with the gene needed for therapy.

2. The virus infects the cell.

3. The gene is injected into the nucleus of the cell.

4. The cell produces the protein required.

Using gene therapy to treat neuromuscular conditions Researchers are investigating the potential of Adeno-associated viruses in the development of gene therapies for a number of neuromuscular conditions. One of the challenges they face is targeting the virus and its genetic cargo to the muscle cells. Researchers are trying to overcome this challenge in two ways. Firstly, they studied many different subtypes of Adeno-associated virus and chose those which infect muscle cells efficiently. Secondly, when researchers make the artificial gene in the laboratory, they add a DNA switch which can only be turned on inside muscle cells. These developments have been used in a number of approaches, some of which are now being tested in clinical trials.

Last year a group of researchers, in collaboration with the French company Genethon, announced the results of a phase 1 clinical trial of a potential gene therapy for limb girdle muscular dystrophy type 2C. Nine participants were divided into three groups with each group receiving a different dose of an Adeno-associated virus carrying a functional copy of the gamma-sarcoglycan gene. The virus was injected into a muscle in one wrist of each of the participants and they were monitored for up to six months. The researchers found that all three participants who received the highest dose had gamma-sarcoglycan protein present in the injected muscle. No participant experienced any serious side effects. Researchers are now doing further studies to plan for a second trial that aims to deliver the virus to a whole limb.

Clinicians are also testing a gene therapy with the potential to inhibit the activity of myostatin. Myostatin is a protein that limits muscle growth, and inhibiting it can lead to an increase in the size, and potentially the strength of the muscles. Studies in animal models have shown that delivering the follistatin gene – which carries the blueprint for a protein that inhibits myostatin – to muscle can have this effect. In a small clinical trial, researchers in the USA are now testing whether an Adeno-associated virus can safely deliver the follistatin gene to the thigh muscle of people with Becker muscular dystrophy or inclusion body myositis, and whether this could increase the size of the muscle fibres in the treated muscle. leading the way forward

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The challenges of developing treatments for Duchenne or Becker muscular dystrophy Duchenne and Becker muscular dystrophy are caused by mutations in the dystrophin gene. One of the challenges of developing gene therapies using an Adeno-associated virus is that the dystrophin gene is too big for the virus to carry – just like an envelope can only hold so many pieces of paper, a virus can only carry a certain amount of DNA. Researchers are currently developing two techniques to address this challenge: building micro-dystrophin genes and developing transplicing technology.

Micro-dystrophin genes are shortened versions of the dystrophin gene.

Genetic material is removed from the gene to make it small enough to fit inside a virus. Importantly, the parts of the gene removed are carefully selected so that the dystrophin protein produced by the shortened gene retains as much function as possible. The resulting protein will be similar to that observed in people with Becker muscular dystrophy, so although the micro-dystrophin protein may not be as functional as a full-size protein, it may reduce the symptoms in boys with Duchenne muscular dystrophy to those found in people with Becker muscular dystrophy.

The technology is currently being tested in a dog model of Duchenne muscular dystrophy and the results are encouraging – with expression of the micro-dystrophin slowing muscle damage and leading to an increase in muscle strength in the treated limb. Next, researchers including Muscular Dystrophy Campaign-funded Prof. George Dickson are planning to test whether the virus can be injected into the bloodstream to reach all the muscles in an animal.

Transplicing technology might one day allow clinicians to deliver a full-size, functional dystrophin protein to the muscles of people with Duchenne and Becker muscular dystrophies. The technology takes advantage of a natural process called transplicing which lets our cells join different pieces of RNA (the carbon copy of DNA which cells use to carry the genetic messages from the nucleus where genes are kept to the cytoplasm where proteins are made) together to make a single protein.

For Adeno-associated viruses to deliver a full-length dystrophin gene, the gene must be divided into two, or even three pieces – hence dual- or triple-transplicing – and each piece inserted into an individual virus. If all three viruses infect a single cell, the parts of the dystrophin gene can be joined together to produce a full-size dystrophin protein.

Transplicing in cells is a rare event however, and researchers are still testing ways to optimise the process. Research is ongoing, but it will be some time before this exciting technology that has real potential can be tested in a clinical trial.

Triple transplicing technology

dystrophin gene

1. The very large dystrophin gene is divided between three Adeno-associated viruses.

2. A cell is infected by the three viruses.

3. The separate pieces of the gene are injected into the nucleus of the cell.

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4. The cell can put the pieces of the gene back together to produce a full-length dystrophin protein.

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4 nucleus

www.muscular-dystrophy.org/research

ADENO-ASSOCIATED VIRUSES AND EXON SKIPPING Adeno-associated viruses can also be used for purposes other than gene delivery. For example, the virus can be used to deliver the genetic information required to produce the molecular patches used for exon skipping.

By choosing an Adeno-associated virus which preferentially infects muscle cells, researchers hope to deliver the molecular patches to where they are most needed. The virus can also act as a steady source of molecular patches, which might reduce the frequency of injections needed for exon skipping. Muscular Dystrophy Campaign-funded work in Prof. Kay Davies’ laboratory which aimed to increase the efficiency of the virus – called U7 – by making small changes to the DNA it carried showed that exon skipping in a mouse model can be long-lasting.

The production of a smaller dystrophin protein was observable for up to one year.

Current studies into the U7 virus are being led by Dr Luis Garcia and Prof. Thomas Voit in France, in collaboration with Genethon.

Their work has seen the approach successfully tested in different animal models of Duchenne muscular dystrophy – both in mdx mice and golden retriever dogs.

Currently their work is focussing on further pre-clinical development of the virus and they aim to start clinical trials in the next few years.

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news Research

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

New FSH Registry is launched A new patient registry for individuals with facioscapulohumeral (FSH) muscular dystrophy, funded by the Muscular Dystrophy Campaign, was launched in May. 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 FSH muscular dystrophy. To find out whether any of these new technologies can be used to treat the symptoms of the condition, they must be tested in clinical trials. However, FSH muscular dystrophy is a rare disease and it can be difficult for clinicians to find sufficient patients quickly enough to start clinical trials without delay.

The registry is funded by the Muscular Dystrophy Campaign and has been established by a team led by Professor Hanns Lochmüller at Newcastle University.

The new online database will contain the information required 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. All the data is stored on a secure server and is only accessible by members of the registry team.

We are calling on everybody in the UK with FSH muscular dystrophy to join the new registry. To join, you can visit the registry website www.fshd-registry.org.uk, where you will be asked to fill in a short online questionnaire about your symptoms and family history. If you would like more details about the registry you can contact the registry curator, Libby Wood, on (0191) 241 8640 or by email on elizabeth.wood2@newcastle.ac.uk

The launch of the FSHD registry marks an exciting time for FSHD patients and we hope the registry will help facilitate clinical research in the UK and globally. Patients and clinicians have worked together to develop a registry that meets the needs of the FSHD community.

I am pleased to be the lead for the registry and am looking forward to seeing it develop in the future. Professor Hanns Lochmüller,, Necastle University

New potential treatment target for myotonic dystrophy type 1 Researchers in Illinois have developed a drug-like molecule which can release a key protein from the clumps of RNA found in the cells of people with myotonic dystrophy type 1.

The molecule can enter cells grown on plastic in the laboratory and once inside is able to release a protein called Muscleblind-like protein 1 (or MBLN1 for short) from the clumps of expanded RNA. This can restore the function of the protein and this may offer a potential target for future treatments.

Myotonic dystrophy type 1 is caused by the inheritance of extra pieces of DNA code. In myotonic dystrophy type 1, a three letter DNA code is repeated many hundreds of times instead of the usual number which is less than thirty.

It is known that RNA – the carbon copy of DNA that carries genetic messages from the nucleus to the cytoplasm where proteins are made – is key to causing myotonic dystrophy.

The extra repeats cause the RNA to get stuck inside the nucleus where it hooks on to certain proteins trapping them inside the nucleus. This leads to the formation of clumps of RNA and protein in the cell nucleus. The proteins including MBLN1 held in these clumps are then unable to perform their normal functions elsewhere in the cell.

Previous work in the field has shown that removing the expanded RNA from the cell can break up the clumps of RNA and release the proteins trapped in the clumps to carry out their function inside the cell.

In this study, researchers have demonstrated that a drug-like molecule can release MBLN1 from the RNA clumps and restore the protein’s function in cells. While this may highlight a potential target for drug development in the future, it will be some time before potential treatments based on this technology could be tested in clinical trials. leading the way forward

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New method to produce embryonic stem cells Researchers in the USA have created embryonic stem cells which are genetically identical to a donor. Clinicians hope that embryonic stem cells could one day be used to treat many different conditions. Using stem cells which are identical to a person could reduce the chances of the treatment being rejected.

Researchers in the USA have, for the first time, produced human embryonic stem cells by replacing the DNA in a human egg with DNA taken from a donor’s skin cell. Researchers grew embryos identical to the donor and this technology could be developed into potential stem cell therapies.

Embryonic stem cells are found in embryos at the very early stage of development and researchers usually isolate the cells from embryos donated for research. The cells have the remarkable ability to specialise into any type of cell, and in the embryo just a few embryonic stem cells eventually give rise to every tissue and cell type in the entire body.

Clinicians hope that embryonic stem cells could one day be used to treat

human diseases including muscular dystrophy and related neuromuscular conditions. However, one of the key challenges with this would be that donor stem cells – just like a donated kidney or heart – could be rejected by a recipient’s immune system after the transplant. The team in the USA has addressed this challenge by producing embryonic stem cells in the laboratory which are identical to the donor; which are much less likely to be rejected.

While the embryonic stem cells produced during this study could overcome the problem of donor cells being rejected, there are other key challenges for researchers to address before these cells could be tested in a clinical trial. Since embryonic stem cells can develop into any type of

tissue there is a risk that injecting the cells into an individual could lead to uncontrolled growth and eventually to cancer. Scientists need to undertake a lot more research to understand how the growth of embryonic cells can be regulated so that they develop exactly into the type of cells or tissue that they are aiming to repair or replace. Most of the conditions we cover are caused by genetic mutations. Before using stem cells for therapy, researchers will need to work out methods to repair the underlying mutation in the cells.

Research is currently ongoing to investigate this process, but it will be some time before researchers will be able to address all the challenges in the same stem cells.

Public back mitochondrial transfer IVF The Human Fertilisation and Embryology Authority has announced the findings of its consultation with the public on mitochondrial transfer IVF – a technique which the Muscular Dystrophy Campaign has spearheaded the development of. It found that people in the UK are broadly in support of the further development of this procedure, provided it is shown to be safe and effective.

Between September and December the Human Fertilisation and Embryology Authority (HFEA) consulted the public on whether the law should be changed to allow mitochondrial transfer IVF to be taken forward into clinical trial. The procedure could potentially prevent mitochondrial disease being transferred to the next generation.

The HFEA interviewed almost 1,000 people, with a further 1,800 completing questionnaires; organised public workshops around the UK and spoke to individuals affected by mitochondrial disease to gauge their views.

In a meeting observed by members of the public, the Authority also agreed to advise Government that, should Regulations be drafted to permit the technique, the following policies and safeguards should be put into place: n

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clinics wishing to offer mitochondria replacement should be specifically licensed by the HFEA to do so the HFEA should approve each use of mitochondria replacement, though Regulations should provide the flexibility to modify this in the future clinics should ensure that follow-up research on the children born takes place

www.muscular-dystrophy.org/research

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mitochondria donors should be thought of as a kind of tissue donor: the resulting child should not have a right to identifying information about the donor, although information exchange and contact could be arranged locally by mutual consent a further assessment of the safety and efficacy should be commissioned by the HFEA once a clinic has submitted an application to carry out one of the techniques. This follows advice from an expert scientific panel that there is no evidence to suggest that mitochondria replacement is unsafe, but that further specific experiments should be conducted.

The HFEA will now advise ministers that there is no evidence that the techniques are unsafe and that public opinion is broadly positive about the introduction of these techniques to the clinic. With a positive recommendation from the HFEA, the Muscular Dystrophy Campaign hopes that Parliament will decide to change the law in 2014 to allow these techniques to move forward.

Links...

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 4813 e: research@muscular-dystrophy.org

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Research news

in brief Sarepta Therapeutics update

At a conference in Washington DC, Sarepta Therapeutics announced that after 74 weeks of treatment, the distance boys in the phase 2 trial of eteplirsen can walk in six minutes is stable. This is encouraging, but it must be noted that the trial is very small – with only six boys in total – and so the results must be viewed with some caution. The company has also announced that they plan to start a larger phase 3 trial early in 2014. We will pass on more details as soon as we receive them.

Sarepta has also signed a contract with the University of Western Australia to work in collaboration with Prof. Steve Wilton (a member of the MDEX consortium) to develop molecular patches to different exons of the dystrophin gene. The CEO of Sarepta Therapeutics, Chris Garabedian, has said that the agreement highlights the company’s plan to develop treatments for all boys with Duchenne muscular dystrophy who could potentially benefit from exon skipping technology.

Glaxosmithkline update In a presentation in Rome, GlaxoSmithKline (GSK) announced that several boys with Duchenne muscular dystrophy taking part in clinical trials of drisapersen (a molecular patch) have received hospital treatment for side effects including thrombocytopenia (a reduction in the number of cells called platelets) or proteinuria (too much protein in the urine which can be a sign of kidney damage).

We contacted GSK to ask for more information and they have assured us that the safety of the boys in the clinical trials is of paramount importance. They also confirmed that all the boys taking part in the trial are being carefully monitored for any signs of side effects and said they are confident that the monitoring programme will make sure that all boys participating in the trial are safe. They also said that any boy who shows signs of these side effects will be admitted to a hospital for treatment and recommended that “anyone participating in a drisapersen study that has questions or concerns should discuss these with their study investigator.”

Report from the Neuromuscular Translational Research Conference On 14 and 15 March nearly 200 people – including scientists, clinicians and representatives from patient groups – gathered in Oxford for the sixth UK Neuromuscular Translational Research Conference. The conference is jointly organised by the Muscular Dystrophy Campaign and the MRC Centre for Neuromuscular Diseases and included a programme of talks and posters presented by international experts in the field of neuromuscular diseases. As well as 25 talks given over two days, over 75 posters were presented in sessions which allowed the researchers to discuss their work informally. The posters highlighted the latest results of research projects and described new techniques being developed in laboratories – with Prof. Nic Wells presenting a novel measure of muscle strength which could measure the potential of exon skipping in a mouse model of Duchenne muscular dystrophy. Prizes were given to the best four posters – with the winner being Muscular Dystrophy Campaign-funded researcher Dr Rebecca Fairclough who presented a poster detailing the search for drugs which might have the potential to increase levels of utrophin in the muscles.

Twigs in a bundle are unbreakable On Friday 21 June, a TREAT-NMD workshop took place at the Wellcome Trust head office in London to discuss how best to assess the benefit of potential treatments for Duchenne and Becker muscular dystrophy.

The meeting was co-sponsored by the Muscular Dystrophy Campaign, and was attended by clinicians, researchers and patient and industry representatives from all over the world.

The timing of the workshop was carefully chosen: at the beginning of March the European Medicine Agency, which is responsible for deciding whether a drug works, started a public consultation on draft guidelines for carrying out clinical trials for treatments for Duchenne and Becker muscular dystrophy. It was therefore important that all parties involved shared their experiences and started talking about their response.

Most importantly, among the participants were representatives from the regulatory bodies themselves. The organisers of the workshop were keen to start the dialogue with them early in the process of bringing treatments to the market to ensure they understand the nature of the conditions and know what it is like to live with them.

The meeting was a fantastic example of how the different stakeholders are now working together to make sure that no time is wasted in driving potential treatments to the clinic.

I am delighted to see this happening and I am pleased to say that patient organisations have a firm seat at the table. Because together we are stronger; together we will make it happen so that one day everybody with Duchenne or Becker muscular dystrophy will have access to an efficient treatment.

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

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So often, people just send off funds raised by charity events and challenges, and trust that it is put into good work. Visiting the lab gave us the opportunity not only to meet the people who are carrying out the research we back, but also to explain to family, friends and all those who support us exactly where their donations go.

Karen Robinson

Behind the scenes: laboratory visits for families Recently, members of the research team visited two laboratories carrying out Muscular Dystrophy Campaign-funded research. We were welcomed into Professor George Dickson’s and Matthew Wood’s laboratories where we were joined by supporters from around the country. The visits gave our families a chance to see firsthand the progress the researchers are making in their pioneering work.

We had time for a quick tour around the laboratories, during which we had a chance to see muscle cells affected by muscular dystrophy through a microscope and also how scientists can isolate a sample of DNA in a test tube.

Neil Robinson

www.muscular-dystrophy.org/research

11 Prof. George Dickson

Royal Holloway University London

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rof. Dickson and his team at Royal Holloway University of London are researching potential treatments for Duchenne muscular dystrophy, including exon skipping technology, and gene therapy. As well as Prof. Dickson, the group heard updates from other researchers working on projects funded by the Muscular Dystrophy Campaign. Dr Linda Popplewell highlighted how gene therapy approaches for Duchenne muscular dystrophy (see page 6 for more information) have shown encouraging results in animal models, while Dr Susan Jarmin talked about the laboratory’s work on myostatin.

Researchers have shown that blocking myostatin activity can have a positive effect on muscle growth, allowing the muscles to grow bigger and potentially stronger.

Prof. Dickson aims to test molecular patches to block myostatin in combination with exon skipping to restore dystrophin, the protein that is missing in Duchenne muscular dystrophy. This combination therapy may prove to be more effective than each treatment on its own.

The group at RHUL was also joined by Dr Rebecca Fairclough from Prof. Kay Davies’ laboratory at the University of Oxford. She provided an update on her work which aims to identify new drugs or molecules with We are very grateful to Professors George Dickson and the potential to increase production of utrophin in the Matthew Wood and their teams for welcoming us into muscles. Utrophin is a protein which is similar to dystrophin their laboratories. The visits give our families a chance and researchers hope that increased production of utrophin may be able to compensate for the lack of dystrophin. to look behind the scenes of scientific research to find

Oxford University

out more about the exciting work that the Muscular Dystrophy Campaign is funding.

Dr Marita Pohlschmidt

In Oxford, Prof. Wood kicked off our visit with an introduction to his lab’s research and the clinical trials that are currently testing potential treatments for Duchenne muscular dystrophy. He then introduced two researchers to give updates on projects funded by the Muscular Dystrophy Campaign. Corinne Betts, a PhD student, discussed her work to improve the efficiency of exon skipping technology.

The current generation of molecular patches are not very good at treating the heart; Corinne is investigating whether attaching small pieces of protein (called peptides) to the molecular patches could improve the efficiency of exon skipping technology, and especially whether it could improve the potential to treat the heart muscle. The improved molecular patches show promise in a mouse model, and the team is now Corinne Betts working to prepare the improved technology for clinical trials. Dr Graham McClorey talked about his work which aimed to identify biomarkers for Duchenne muscular dystrophy. Biomarkers are molecules which are easy to measure and are altered by disease. In a mouse model, the team has discovered short pieces of RNA – called microRNAs – in the blood, which may have the potential to be used to monitor the progression of Duchenne muscular dystrophy.

Lab coats photo: jeangill/istock

A tour around the laboratories At both universities, the talks were followed by a tour – giving everybody the opportunity to look around a laboratory and to see some of the techniques used by researchers in their work. We used microscopes to look at muscle cells growing We had an enjoyable and fruitful experience at Oxford. Professor on plastic, and were shown how muscle Wood’s research investigating attaching peptides to the current samples can be examined for the presence of exon skipping drugs looked excellent and will hopefully improve the dystrophin protein. And at Royal Holloway, the efficiency and effectiveness of this medication (especially Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign in improving the uptake in the heart), We are delighted to have demonstrated how scientists can purify contributed with a donation to assist Professor Wood’s work.

DNA in a test tube.

Chris Govender leading the way forward

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www.muscular-dystrophy.org

Put Thomas in the winning seat

Text THOM13 5 to 70070 to give £5 to drive research forward for boys like Thomas

Thomas is five years old.

He’s mad about cars, and his absolute favourite movie in the whole world is Disney’s Cars. He wants to be a racing driver.

Thomas can walk but he can’t run or jump like his friends can. He has his own ‘ride’ – a manual wheelchair for when his legs are tired. You see, Thomas has the severe muscle-wasting condition called Duchenne muscular dystrophy.

It affects mainly boys, and causes muscles in the arms, legs, lungs and heart to weaken and waste over time. Boys are in wheelchairs at 12 and before they turn 30, Duchenne muscular dystrophy is likely to have stopped their hearts.

There is no cure, but scientists are on track to find treatments that could make Thomas’ and thousands of other boys’ futures so much stronger.

Success here would fuel Thomas’ dream and put him in the winning seat.

But we can’t do this without your help. If you give just £5, you can help us keep this vital research going. Right now.

www.muscular-dystrophy.org/research