Target Research October 2011

Target Research November 2011

Exon skipping

innovation

A new way to deliver molecular patches to the muscles

Finding answers

CUTTING-EDGE

Introducing our nine new research projects A must read

Preimplantation genetic diagnosis One family’s quest to have healthy children

Also inside‌experts answer your questions and read about all the latest research and clinical trial news

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

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.

Adeno-associated viruses (AAV) – see page 7.

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.

Anticipation – in genetics this refers to a genetic condition that appears earlier and with increased severity with each successive generation. Examples include myotonic dystrophy and Huntington’s disease.

Chromosome – cylindrical shaped bundles of DNA found in the cell nucleus. They consist of long, threadlike strands of DNA coiled upon themselves many times. We inherit 23 chromosomes from our mother and 23 from our father Creatine kinase – a type of protein found in muscle. Some forms of muscular dystrophy are associated with high levels of creatine kinase in a blood test because when muscles are damaged the creatine kinase leaks into the bloodstream.

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

Dominantly inherited – a genetic condition in which a single abnormal copy of a gene causes disease, even though a good copy of the gene is also present. We inherit one copy of each gene from our mother and one from our father.

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.

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

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

Gene – a portion of DNA containing the

www.muscular-dystrophy.org/research

instructions for the production of a specific protein.

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

MRI (magnetic resonance imaging) – a noninvasive body imaging procedure that uses powerful magnets and radio waves to construct pictures of the internal structures of the body.

Molecular patch – see page 7.

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

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

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

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.

RNA – a substance very similar to DNA. When a gene is ‘switched on’ RNA carbon copies of the gene are made which move to the protein producing machinery of the cell.

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.

Whole genome sequencing – a laboratory process that determines the order of the more than three billion units that make up our entire genetic code. Also called next generation sequencing.

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

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

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

ISSN 1663-4538 Muscular Dystrophy Campaign 61 Southwark Street London SE1 0HL t: 020 7803 2862 e: hello@muscular-dystrophy.org w: www.muscular-dystrophy.org

Registered Charity No. 205395 and Registered Scottish Charity No. SC039445 Printed on PEFC paper, produced at a mill that is certified with the ISO14001 environmental management standard Enclosed into a bio-degradeable polybag

3 Welcome to the new look Target Research! I’m delighted that from now on we will bring you four issues per year which will give us the chance to keep you more up to date with the fast moving world of research.

Welcome On the cover The DNA double helix. Turn to page six to find out how one research team in Oxford is harnessing DNA technology to develop treatments.

Target Research October 2011

Exon skipping

There has been a definite buzz in the office over the past few months – my phone has been running hot and my inbox has never been so full with questions and comments from families! This was all in response to the promising results of the UK exon skipping clinical trial for Duchenne muscular dystrophy that was widely reported in the media in July. You can read about these results on page 10 and find answers to some of the questions you might have on the Ask a Scientist page. This progress is even more exciting because I’m sure there will be a knock on effect for people with other neuromuscular conditions (see page 11). One of the most rewarding parts of my job is answering your research questions, so if I can help you to understand the latest developments and what they mean for you, please do get in touch.

The development of exon skipping will not stop there though. Scientists are now working in the lab to improve the technology so that this potential therapy may be more effective for more patients in the future. As such, one of the highlights of this issue is an update on a research project we have been funding at the University of Oxford (page 6). This project involves an innovate method to more effectively deliver exon skipping therapy to the muscles.

INNOVATION

A new way to deliver molecular patches to the muscles

Finding answers

CUTTING-EDGE

Introducing our nine new research projects A MUST READ

Preimplantation genetic diagnosis One family’s quest to have healthy children

Also inside…experts answer your questions and read about all the latest research and clinical trial news

Also in this issue you will find details of our nine cutting-edge new research projects and there are updates on the latest research news from the UK and around the world. You can also read on page 12 a moving interview about one woman with myotonic dystrophy’s quest to have children without passing on the condition.

I hope you enjoy reading the new Target Research magazine and I’d love to hear what you think.

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

Contents 4 New research projects - introducing the nine cutting-edge projects granted

funding this year 6 Exon skipping innovation - a new way to deliver molecular patches for

Duchenne muscular dystrophy 10 Research and clinical trials - news from the UK and around the world 12 Preimplantation genetic diagnosis - IVF technology fulfils a dream 14 Ask a scientist – your questions answered by experts in the field 15 Thinking ahead – our strategy going forward from Dr Marita Pohlschmidt,

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

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Finding answers...

New research projects Dr Julia Ambler Head of Grants Muscular Dystrophy Campaign

Project Grants: Moving closer to an effective treatment for spinal muscular atrophy Researchers at the University of Edinburgh led

by Professor Thomas Gillingwater will increase our understanding of the cause of spinal muscular atrophy in this project.

In spinal muscular atrophy the motor neurons (the nerves that connect the spinal cord to muscle) break down due to low levels of a protein known as ‘survival of motor neuron’ (SMN). It is not well understood why a lack of this protein causes the motor neurons to break down.

This project will test whether a very important, but often overlooked, type of cell that supports motor neurons (known as glial cells) contributes to disease onset and severity. This project will improve our understanding of what cell types need to be targeted in order for a new potential treatment, such as the gene therapy approaches currently being developed, to be successful.

www.muscular-dystrophy.org/research

5 In this pilot study fifteen people with McArdle’s disease in the UK, Denmark and the USA will receive treatment for six months to gather the first evidence on whether this drug improves symptoms. If successful, this could lead to a larger clinical trial to test this drug in more detail and a new treatment may then become available for people with McArdle’s disease.

Developing a utrophin drug for Duchenne and Becker muscular dystrophy

Each year the Muscular Dystrophy Campaign invests more than one million pounds into research. This includes funding for 25 to 30 research projects which aim to increase our understanding of the underlying causes of many of the different types of muscle disease and develop effective treatments.

A rigorous selection process ensures that we only support the highest quality research and we are proud to announce the addition of nine exciting new projects to our portfolio this year - five project grants and four PhD studentships.

A pilot clinical trial for McArdle’s disease In this project Dr Ros Quinlivan at University College London will lead an international clinical trial to test, for the first time, the safety and effectiveness of a drug for McArdle disease.

McArdle’s disease is a very rare condition caused by the lack of a particular enzyme that is important in the process of producing the fuel needed by muscles when exercising.

There is a similar enzyme present in the brain and it has been shown that giving a particular drug to an animal model of McArdle’s disease switches on the brain enzyme in the muscle.

Professor Dame Kay Davies’ laboratory at the University of Oxford will continue their work to develop an effective drug therapy which increases the amount of a protein called utrophin in the muscles. This approach has the potential to treat all boys with Duchenne and Becker muscular dystrophies, no matter what their genetic diagnosis shows.

It is thought that utrophin, a protein naturally present in our body in small amounts, may be able to compensate for the dystrophin protein that is missing in boys with Duchenne muscular dystrophy and reduced in those with Becker muscular dystrophy.

With our continuous support over the past 20 years, the lab has already been successful in developing a drug with the potential to increase levels of utrophin. It dramatically reduced muscle weakness in mice with Duchenne muscular dystrophy.

However, when tested in people in clinical trial it was not efficiently absorbed into the bloodstream. This project aims to identify and develop more effective follow-up drugs.

Improving the diagnosis of mitochondrial disease In this project Dr Shamima Rahman at University College London aims to identify new genetic changes causing mitochondrial diseases.

Currently approximately 80 percent of patients with mitochondrial disease do not receive a genetic diagnosis.

The lack of a genetic diagnosis leads to uncertainty about how the disease

will progress and how it might be passed on to future generations. Most importantly, lack of understanding of the precise causes is inhibiting the development of therapies for these currently incurable diseases.

Mitochondrial diseases are caused by the energy producing structures in the cell - called mitochondria - not working efficiently. This can be caused by changes to the 13 genes that are contained within the mitochondria itself or changes to genes within the – control centre of the cell – the nucleus that contains more than 20,000 genes.

It is thought that the undiagnosed cases of mitochondrial disease are likely to be caused by changes to genes in the nucleus. The scientists will use cutting edge technology – whole genome sequencing – to identify new genetic changes causing these conditions.

Combination treatment approach for Duchenne muscular dystrophy and other conditions In this project Professor George Dickson at Royal Holloway - University of London will combine exon skipping with another approach to boost its effectiveness.

Exon skipping restores the production of dystrophin by masking the genetic change that causes the condition with small pieces of DNA called molecular patches. This approach is now in clinical trial with promising results (see page 10).

In this project molecular patches will also be used in a different way – to block the action of a hormone called myostatin. Myostatin normally limits the growth of muscles, so they propose to reduce its amount in an animal model of Duchenne muscular dystrophy to increase the size and strength of the muscles. This combination therapy may prove to be more effective than each treatment on its own for Duchenne muscular dystrophy. Importantly, the myostatin treatment on its own may also prove to be effective for other types of muscular dystrophy.

leading the way forward

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PhD Studentships: Understanding two different types of limb girdle muscular dystrophy

amount of a protein called LARGE which may be able to compensate for the changes to FKRP.

Professor Kate Bushby at Newcastle University will supervise a project to continue her work on the limb girdle muscular dystrophies (LGMD).

Identifying new genes responsible for congenital muscular dystrophies and congenital myopathies

There are at least 21 different types of LGMD. The precise mechanisms underlying two of these – LGMD 2B and 2L – are currently unclear making it harder to establish clear targets for designing therapies. It is thought that the genes causing these conditions are both involved in the same process – muscle repair after injury.

Professor Francesco Muntoni, University College London will supervise this project that aims to improve the diagnosis of congenital muscular dystrophies and myopathies.

This project aims to understand how these genes function and relate to each other which will bring a new level of understanding of LGMD2B and LGMD2L. This research could result in new therapeutic approaches to improve muscle repair and thereby treat these types of muscular dystrophy.

The congenital muscular dystrophies and myopathies are a diverse group of conditions and numerous gene changes have already been found to cause them. However, there are still many people for whom a precise genetic diagnosis cannot be given as they do not have a change in one of the known genes.

These projects were selected for funding not only by our committee of expert scientists and clinicians, but our hard working Lay Research Panel also carefully considered the proposals and had a say in what they thought was important from the point of view of people directly or indirectly affected by muscle disease.

This project aims to using cutting edge technology – whole genome sequencing – to search for new causative genes.

Being able to give a precise genetic diagnosis has immediate benefit for families, allowing them to have genetic counselling and a more accurate prediction of how the condition will progress allows them to plan for the future. Knowing the genetic cause will also allow the identification of therapeutic targets.

Developing an animal model to test therapies for certain types of muscular dystrophy

Improving delivery of molecular patches to the heart

Dr Susan Brown, Royal Veterinary College will supervise a student to study two conditions caused by changes in a gene called FKRP. It is not well understood why a change to one part of the FKRP gene can cause a very severe form of congenital muscular dystrophy while a change in a different place can cause a milder form of limb girdle muscular dystrophy (type 2I).

Professor Dominic Wells at the Royal Veterinary College will supervise this project to improve exon skipping technology for Duchenne muscular dystrophy.

They will use an animal model to try to better understand these conditions and identify where it would be most effective to intervene with a therapy. They also plan to investigate the viability of possible therapeutic approaches such as increasing the www.muscular-dystrophy.org/research

into muscles. Improving the delivery of molecular patches has the potential to vastly improve the effectiveness of exon skipping and may also allow the use of lower doses which may be safer and cheaper.

Exon skipping is currently in clinical trial as a potential treatment for Duchenne muscular dystrophy. It is proving to be a challenge, however, for sufficient amounts of the molecular patches to travel from the blood stream where they are injected, into all the muscles of the body and particularly the heart.

This project aims to investigate ways of making the blood vessels more ‘leaky’ so that more molecular patch is able to pass from the blood stream

Help us make a difference...

It is only through your contributions that we can continue to fund the vital work that takes us closer to finding treatments and cures for muscle disease. If you want to make a donation here’s how to contact us: Muscular Dystrophy Campaign, 61 Southwark Street, London SE10HL t: 020 7803 4800 w: www.muscular-dystrophy.org/waystodonate e: donations@muscular-dystrophy.org

Innovation

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Exon-skipping A new way to deliver molecular patches for Duchenne muscular dystrophy

Dr Aurélie Goyenvalle University of Oxford

Since the first clinical trial for exon skipping began in 2006, there has been great anticipation about this potential treatment for Duchenne muscular dystrophy. The trials carried out so far have shown promising results, but scientists are still facing challenges in trying to deliver as much of the molecular patch as possible to all the muscles of the body.

Dr Aurélie Goyenvalle, a Muscular Dystrophy Campaign-funded researcher and recipient of the first ‘Patrick Research Fellowship’, describes some of the work she has been doing to overcome these challenges over the past two years in Professor Dame Kay Davies’ laboratory at the University of Oxford. leading the way forward

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What is exon skipping?

The instructions for all the proteins that make up the body are contained in DNA, in ‘sentences’ called genes. When there is a change to the instructions, this is called a mutation and can prevent a protein being produced.

Exon skipping is a technology that encourages the cell to skip-over part of a gene. Small pieces of DNA called antisense oligonucleotides (AOs) or molecular patches are used to mask the area of DNA that you want to skip.

For Duchenne muscular dystrophy exon skipping would help the cells to restore production of dystrophin protein, albeit with a piece missing in the middle.

Scientists have very good reasons for pursuing this approach for Duchenne muscular dystrophy. Traditionally gene therapy uses a virus to deliver a healthy copy of the whole gene. This is difficult for Duchenne muscular dystrophy because dystrophin is the biggest gene we have and it simply doesn’t fit

Delivering molecular patches

Although the clinical trial results of exon skipping have been promising (see page 10), several challenges have been identified. It can be difficult to get enough of the molecular patches into all of the muscles of the body which make up about 40 percent of our body mass. From the research on animals in the laboratory it also seems to be particularly difficult, despite repeated treatments, to get the patches into the heart. Finding a new way to deliver the patches, might provide a solution to this problem.

In Professor Kay Davies’ laboratory at the University of Oxford we have been investigating a type of gene therapy that uses viruses to deliver into muscle the instructions for making the molecular patches. These particular viruses, called adeno-associated viruses (or AAVs) have been modified so they don’t cause any harm to the human body. AAVs are particularly efficient at infecting muscle cells and the heart so could make the perfect delivery system for getting the patches to these tissues.

Dr Aurélie Goyenvalle

Once the virus is inside the muscle cell it delivers a small piece of DNA containing the instructions for making the molecular patch into the nucleus of the cell. The cell then makes many copies of the molecular patch in-situ over a long period of time, possibly even for life. It would be expected that this approach would have a much longer lasting effect than the exon skipping therapy currently in clinical trial which involves weekly visits to the clinic for injections.

Virus inside a virus. Fortunately, dystrophin contains many repeated segments in the middle that are not essential for the protein to work at least to some extent.

This is the case for Becker muscular dystrophy; a smaller dystrophin protein is produced in the muscles. Individuals with Becker muscular dystrophy have milder symptoms and are often still able to walk into their 40s and 50s.

So exon skipping aims to transform the severe symptoms of Duchenne muscular dystrophy into the more mild symptoms of Becker muscular dystrophy.

www.muscular-dystrophy.org/research

We worked with a particular mouse model called a ‘double knock-out mouse’ that has severe symptoms similar to Duchenne muscular dystrophy. These mice are missing not only the dystrophin protein, but also a related protein called utrophin. These mice have a much shortened lifespan and tend to have a curved spine which gives them the appearance of a humped back, progressive wasting of their muscles and problems with mobility. This model makes it very easy to spot when a therapy is working because improvements in lifespan and symptoms can be easily observed.

Photograph of a double knock-out mouse (left) with a curved spine and a reduced size compared to a virus treated mouse (right) looking healthy at 12 weeks of age.

Already, some exciting results have come out of this work. We found that after a single injection of the virus the results were striking. Not only was there a significant increase in the amount of dystrophin in the muscles of these mice, but their symptoms also improved. The humped back was prevented, mobility improved and lifespan increased from three months to more than one year and still counting.

Gene therapy using adeno-associated virus (AAV)

Virus binds to cell membrane and enters the cell Virus injects DNA containing instructions for making the molecular patch into the nucleus of the cell

Cell makes molecular patches

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Skipping multiple exons

Another advantage we can anticipate by using viruses to deliver molecular patches is that more than one exon might be able to be skipped at once.

This has proven technically challenging using regular molecular patches since all of them have to enter the same cell at the same time to act collectively.

However, this could be achieved by putting the instructions for more than one molecular patch inside each virus.

There are several reasons why you might want to skip more than one exon in one go. Firstly, for some boys it will be necessary to skip more than one exon to repair the gene and using a virus might be the most efficient way of doing this.

Secondly, the different mutations that cause Duchenne muscular dystrophy each require skipping of different exons, and therefore the design and testing of many specific molecular patches. The development of all of these different molecular patches will be costly and time consuming.

However, by skipping multiple exons it might be possible to develop one drug that treats a larger proportion of boys. For example, approximately 70 percent of the dystrophin mutations are found in a ‘hot-spot’ around exons 45 to 55. The skipping of an entire stretch of exons from 45 to 55 could therefore be applicable for a very large group of patients. Not only would this be a more economically attractive prospect for drug companies but some of the major hurdles regarding regulatory approval in getting this technology into the clinic could be overcome.

To investigate multiple exon skipping we have put the instructions for several different molecular patches into a virus and we are testing these both in patients’ cells grown in a Petri dish and in a mouse model. The initial results are encouraging and while this work is still ongoing, it has provided proof of principle that multi-exon skipping could be a viable way forward.

How the funding from Muscular Dystrophy Campaign has made a difference With the support of the Muscular Dystrophy Campaign, we have been able to achieve results that show how viruses could be used to deliver one or more molecular patches. This could help to improve the delivery of the patches not only to the muscles, but importantly to the heart as well.

The development of a multi-skipping approach could provide an alternative to the highly personalised medicine approach of one mutation: one patch and therefore be applicable to a much larger proportion of patients with a quicker transition from the bench to the bedside.

What are the next steps?

We are continuing to work closely with our collaborators at Genethon – a large research institute near Paris focusing on the development of gene therapy for rare diseases. They have expertise in conducting AAV gene therapy clinical trials and in partnership with other research groups in France they are planning clinical trials of this gene therapy approach for Duchenne muscular dystrophy which are scheduled for 2013. The research in Oxford has been instrumental in moving this gene therapy approach forward towards clinical trial.

On a personal level, the Patrick Research Fellowship award is allowing me to carry out some very promising research and the publication of the results will enable me to further my career. This project has put me in a strong position to move closer to my goal of making the transition from post-doctoral research trainee to independent investigator so that I can continue to make a contribution to finding effective treatments for muscular dystrophy – a field that I am passionate about.

The Patrick Research Fellowship is a brand new award that has been funded through the generous support of Mr Alexander Patrick and his family. It has been used to support the career of a senior post-doctoral researcher, Dr Aurelie Govenvalle, working in the field of Duchenne muscular dystrophy research. Mr Patrick and his family have been long-term supporters of the Muscular Dystrophy Campaign.

When asked about the Fellowship Mr Alexander Patrick said: As founder members of the Muscular Dystrophy Campaign, the Patrick family have been pleased to support the Charity through the Patrick Trust.

Following a major gift of money to Muscular Dystrophy Campaign, the trustees are delighted that part of this funding is to be allocated to Professor Dame Kay Davies’ exon-skipping project. The high standards achieved by Kay and the promising research to be carried out by Dr Aurélie Goyenvalle give us great hope for the future. leading the way forward

10 Keeping up to speed with clinical trials

Research

news

Encouraging results of UK Duchenne exon skipping clinical trial published

The full results of the UK exon skipping trial for Duchenne muscular dystrophy have been published showing that dystrophin - the protein missing in boys with Duchenne muscular dystrophy - was produced with no significant side effects. The Muscular Dystrophy Campaign has invested more than one million pounds into the development of this therapy over the past 20 years.

The trial involved delivering a ‘molecular patch’ (AVI-4658 now called eteplirsen) developed by British and Australian scientists to the whole body by injection into the bloodstream. The molecular patch is designed to mask a portion of the dystrophin gene called exon 51, and could potentially be used to treat about 13 percent of boys with Duchenne muscular dystrophy.

The 19 boys in the trial had weekly intravenous infusions (needle into the vein) for 12 weeks at one of six different doses. Three of the boys receiving higher doses of the drug had a strong response; they had 15, 21 and 55 percent of their muscle fibres containing detectable amounts of dystrophin protein after treatment (compared to less than three percent before treatment). There were also indications that the new dystrophin was working correctly in muscle. www.muscular-dystrophy.org/research

After treatment with AVI-4658 less inflammation was seen in the majority of patients in the high dose groups.

In Duchenne muscular dystrophy inflammation can contribute to muscle degeneration, so reduced inflammation is encouraging.

There were no significant changes in lung or muscle function throughout the study. Creatine kinase levels also stayed the same, as did the distance walked in six minutes. This was not surprising given the short duration of the study.

Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign commented on the results “We have fought to find a treatment for this devastating condition for the past 50 years. Today we can say with real confidence that we’re going to win that battle. Parents of these boys can have real hope for the future.”

AVI Biopharma has started the next phase of the clinical trial in the US to test higher doses of eteplirsen for 24 weeks. The results of this trial should be available in the middle of next year. It is intended that the results will be used to determine the best dose for testing in a large, international phase 3 trial that is expected to start in the second half of 2012. AVI Biopharma have given assurances that the UK will be included in the phase 3 trial. This trial should give clearer answers about the effectiveness of this treatment.

We know that our supporters want to keep a finger on the pulse of what potential treatments are being tested in clinical trial around the world and find out if there’s a trial nearby to potentially take part in. So over the past year we have been working to produce a section on our website where you can find out all the information you want and need to know about clinical trials for your condition worldwide.

With the help of a team of wonderful young scientists from around the country who volunteered to help us write lay summaries we have now achieved this. There are now more than one hundred summaries of clinical trials on our website covering 22 different neuromuscular conditions. You can search for trials for your condition and filter them by the location of the trial.

Opening up the summary gives you an explanation of the aim of the trial, how the trial could benefit patients, who can take part and how to get involved.

An example of one such clinical trial is a study testing a drug called olesoxime in people with spinal muscular atrophy types 2 and 3 in the UK and six European countries.

However, not all the studies involve

11 testing a new treatment. For example, a study might recruit people with a particular condition to donate blood so that researchers can study the condition in the laboratory. This may lead to the development of promising treatments. Other studies are focused on monitoring the natural progression of conditions which can have a direct impact on improving standards of care and will also put the infrastructure in place for conducting clinical trials in the future.

Check it out and let us know what you think (contact details on page 3) www. muscular-dystrophy.org/clinical_trials Avoiding painful biopsies Research supported by the Muscular Dystrophy Campaign at the Dubowitz Neuromuscular Centre in London has shown that non-invasive MRI scans are a reliable way of assessing the muscles of boys with Duchenne muscular dystrophy. This has the potential to replace some of the biopsies currently taken during clinical trials.

This is good news, not only because biopsies are unpleasant for patients, MRI scans also have the advantage of being able to assess the muscles throughout the body rather than a tiny sample taken by biopsy.

In clinical trials this might give a more accurate overall picture of how beneficial the treatment is.

MRI is currently a very active area of research – the MRC Centre for Neuromuscular Diseases (Newcastle and London) has a team dedicated to developing advanced MRI techniques for a wide range of neuromuscular conditions. This research will improve diagnosis because the pattern of muscle damage seen on MRI can give the clinician clues about what condition a person might have and the scans can also be used to monitor the progression of the condition.

MRI is not the only approach being investigated to replace biopsies. We are also funding research in Dr Matthew Wood’s laboratory at the University of Oxford to find substances in the blood – called ‘biomarkers’ – that could be used to provide an accurate measure of muscle damage as an alternative to biopsies. This research focuses on

tiny pieces of genetic material called micro-RNAs. These recently discovered molecules are a hot topic in science as they have been shown to be involved in almost all biological processes and it may also be possible to take advantage of them as a therapy (please see below).

Our bodies have over 1000 different micro-RNAs, and this research is searching for those that are increased or decreased in boys with Duchenne muscular dystrophy. These micro-RNAs could then serve as an indicator of muscle damage and be used to monitor improvements after treatment in clinical trials. Although this project has only been running for one year, several promising candidate micro-RNAs for further investigation have been identified.

A potential gene therapy approach for FSHD and other conditions Two research papers published within a month of each other, by researchers in Italy and the US, have shown that it is possible to reverse the symptoms of facioscapulohumeral muscular dystrophy (FSHD) in a mouse model using a gene therapy approach.

This research took advantage of a natural process in the body which turns genes off - called ‘RNA interference’.

It involves introducing into cells tiny pieces of genetic material called ‘microRNA’ that are designed to specifically switch off a particular gene. Adenoassociated viruses (AAV) were used to deliver micro-RNA into the cells of mice. Both studies reported that after treatment, the mouse muscles not only looked healthier under a microscope but their muscle size and strength was improved.

The techniques used may also be applicable to some other dominantly inherited muscle conditions such as myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), Charcot-MarieTooth disease and some types of limb girdle muscular dystrophy, congenital muscular dystrophy and congenital myopathy. However, each affected gene will need to be looked at on a case by case basis, and researched in the laboratory before it is decided if it could be amenable to RNA interference.

RNA interference is very new technology and although there have been promising results from animal models, in particular for neurodegenerative conditions, no drugs have reached the clinic yet.

Therefore, it may be several years before it is ready for testing in patients. In particular the underlying mechanism causing FSHD is still not fully understood so how the results of this research will translate into humans requires further investigation.

New lead for myotonic dystrophy treatment Researchers in Spain recently identified a new way to block the effect of the genetic change that causes myotonic dystrophy type 1 (DM1). The researchers used a fruit fly model of DM1 to screen millions of small pieces of protein which are called ‘peptides’.

The researchers then narrowed the promising peptides down to one and tested it in a mouse model. They injected it into mice with myotonic dystrophy and the muscles of the treated mice appeared healthier under the microscope.

There are several different approaches being developed for myotonic dystrophy in laboratories around the world. This new research is important because it brings forward a new strategy to target the genetic cause of myotonic dystrophy which has the potential to go forward to clinical trial.

The more promising ways we have of tackling the condition the more likely one will be successful in the end.

Professor Darren Monckton, myotonic dystrophy researcher at the University of Glasgow said: The data are certainly very encouraging and if replicated in humans would be expected to be therapeutically beneficial.

The next step will be to show that such a peptide could be delivered effectively at the dose required in humans. At the very least though, the study provides important biological information and a solid lead for drug development.

leading the way forward

12 Dexter now has the same chance of being healthy as most other children being born.

He is no designer baby.

Cutting edge technology fulfils a dream Preimplantation genetic diagnosis (PGD) is a technique that was developed in the early 90s to enable people with a genetic condition running in their family to avoid passing it on to their children.

Couples undergo standard in vitro fertlisation (IVF) during which eggs are fertilised by sperm outside the body.

The fertilised eggs are allowed to grow until they are embryos consisting of eight cells. Then one or two cells are removed and are tested for a specific genetic condition. Only embryos that test negative for the condition are put back into the womb. The DNA of the implanted embryo isn’t changed in any way; it is a selection process to choose an embryo that hasn’t inherited the faulty gene.

The usual success rates of IVF have to be contended with by couples undergoing PGD and there are also fewer embryos for transfer back into the womb due to the selection process.

The chances of having a baby following PGD are around twenty percent per cycle, so many cycles may be necessary before a successful outcome is achieved.

The Human Fertilisation Embryology Authority (HFEA) tightly regulates which conditions can be tested for and currently PGD is available for 185 genetic conditions including many neuromuscular conditions. Licences are only issued to experienced fertility clinics for them to test for serious, debilitating and life threatening genetic conditions.

Going down the route of PGD requires planning prior to starting a family and detailed knowledge of the exact www.muscular-dystrophy.org/research

13 genetic cause of the condition is essential. However, up to a third of people with a neuromuscular condition don’t have a genetic diagnosis because they don’t have a change in any of the genes known to cause their symptoms.

Research to identify more genes involved in neuromuscular conditions will open up PGD as an option for more families in the future. This is one reason why it is so important for the Muscular Dystrophy Campaign to continue funding research in this area (read about some of these projects on page 4&5).

PGD is a complex issue and even if it is available for a condition, it’s not for everybody. Some people may not wish to consider it for religious reasons, for others the time, cost and upheaval involved rules it out.

Shona Davison was diagnosed with myotonic dystrophy at the age of 28, she has already had one baby using PGD and is pregnant with a second. We asked her about the issues she faced relating to PGD. What made you go down the route of PGD? We considered a number of options including adoption, prenatal testing and then possibly having a termination, or just leaving the baby’s health to luck.

I didn’t think I would be able to cope with the emotional trauma of potentially having multiple terminations but leaving the child’s health to luck also wasn’t an acceptable option for us. I didn’t think it was fair for our desire to have a child to come ahead of the child’s welfare, especially when I knew that due to something called ‘anticipation’ in myotonic dystrophy, if my child inherited the condition they would have much more severe symptoms than me.

We seriously considered egg donation in Spain (due to the shortage of egg donors in the UK), when it looked like PGD wasn’t going to work for us.

You’ve been through six cycles of PGD (three for the first and three for the second pregnancy), which must have been stressful,

yet you have been very open about the process with your blog and appearing in the BBC documentary “What if my baby is born like me?” - what made you decide to share your personal journey?

I didn’t like that no one told me about PGD when I was diagnosed with myotonic dystrophy even though I specifically asked my consultant about my options for starting a family. I was only told about prenatal testing. How can people make decisions without all the information? My main goal was to raise awareness so that people can make informed choices.

An additional benefit is all the support I received during my sixth cycle. I have also been able to offer support to others. I get a lot of emails from people going through PGD at the moment.

What would you say to a couple who are trying to decide whether to go ahead with PGD? Be prepared for an emotional rollercoaster. You will need support so I personally think it is good to tell some close friends what you are doing. It is too hard for any couple to do it all on their own.

It’s easy to see looking at a photo of Dexter the positive side of PGD, but what are the negatives?

The cost is a major barrier for many people. My first three cycles were funded by the NHS, but still they were expensive for us as I had to travel to London from Sheffield for every appointment. I work for myself so there were also lost earnings to consider when I couldn’t work. After Dexter was born we got no more NHS funding, so we paid for cycle four, five and six ourselves. It wasn’t easy to raise the money and it feels like a big weight is lifted now we have finished.

Another negative is the effect it has had on my career. I am ambitious and it is frustrating that so much time, money and emotional resource has been sidetracked by IVF. However ambitious I am though, my desire for a successful career has always been pretty minor compared to my desire for a family.

From a positive perspective, Steve and I have now achieved our main dream in life. We have Dexter and his sister will be born in November. It has been worth every penny, every hospital appointment and every tear. There have been a lot of tears shed in our house over the last six years. Not just sad ones, happy ones too.

IVF puts a lot of pressure on your relationship. Steve and I always reminded each other why we were arguing more than normal. We were under an extreme amount of stress.

In the long run, having gone through such a challenging time has brought us closer together.

Has anyone criticised the choice you and your husband made?

I was aware of how controversial PGD can be and so was a bit unsure about starting my blog. I had no negative comments on my blog though there were a couple on online forums and twitter. One man was talking about people wanting to live forever. I put those sort of opinions down to ignorance about what PGD is actually used for. Dexter now has the same chance of being healthy as most other children being born. He is no designer baby.

It has been worth every penny, every hospital appointment and every tear.

There have been a lot of tears shed in our house over the last six years. Not just sad ones, happy ones too.

Links...

Read Shona’s blog w: www.apgdblog.blogspot.com The HFEA website w: www.hfea.gov.uk/preimplantationgenetic-diagnosis/html leading the way forward

14

Ask a Scientist The Muscular Dystrophy Campaign research team is always available to answer any questions about research. Questions we don’t know the answer to, we refer to our network of scientists and clinicians working in the field. In this article we posed some of the questions we have received recently to top researchers for further expert opinions.

Q. I have Becker muscular dystrophy

and I have been offered stem cell treatment in China. They say that for $24000 USD they can transplant neural and mesenchymal stem cells by lumbar puncture and intramuscular injection. They claim to be able to improve my muscle strength by at least 20-30 percent. Please can you help me to understand if I should go ahead with this?

Anonymous

A. We fully understand that people

with serious, debilitating and often lifethreatening neuromuscular conditions are willing to try anything that might offer them a treatment for their condition. A lot of people feel that they don’t have anything to lose by trying such options.

However, we are deeply concerned about unregulated clinics abroad selling stem cell transplants for large sums of money without any evidence on their effectiveness or safety. As such, they may be at best ineffective, or at worst dangerous and potentially fatal. There are numerous reports of people suffering serious complications, including several deaths, after treatment at unregulated stem cell clinics abroad.

Although there have been some promising results in animals using stem cells for neuromuscular conditions, there have not yet been any clinical trials in humans. It will probably be a long time yet until the work on stem cells currently ongoing in the lab can be translated into reality in the clinic.

www.muscular-dystrophy.org/research

We want to see properly tested stem cell therapies available on the NHS in the earliest possible timeframe, and not prematurely in the private sector for the few who may feel they can afford to take the risk.

We urge anyone considering taking a chance on any unproven therapy to carefully consider the evidence on potential benefits and the risks. There is a website by the International Society for Stem Cell Research that gives a list of questions you should ask the clinic to gather all of the relevant information before making a decision: www. closerlookatstemcells.org. TREAT-NMD also has an online guide called hope versus hype with information relating specifically to stem cell treatments for neuromuscular conditions www.treatnmd.eu/resources/ethics/stem-cell/ hope-versus-hype.

Dr Marita Pohlschmidt, Director of Research, Muscular Dystrophy Campaign

Q. We have been listening to the

news about Duchenne today and see that the exciting exon skipping breakthrough only appears to apply to boys with the mutation in exon 51. Do you have any idea when this treatment might be available to boys with rarer mutations? Would it be fair to say that if you can 'patch up' a genetic fault in one part of the gene, then it would be a similar procedure in another part or it is more complicated than this?

Catherine Rimington Wilson

15

A. Exon 51 was chosen for the first

study because skipping this exon would be relevant to about one in ten boys with Duchenne muscular dystrophy.

While the MDEX/AVI-4658 trial results are very promising, with dystrophin production undeniably restored in some boys, no clinical benefit has been seen after this short safety-orientated study (see page 10). It is difficult to say when rare exons will be addressed.

Molecular patches for other dystrophin exons are being considered for subsequent trials and some are already in development based upon how many boys could benefit from them.

Skipping an exon associated with a less common mutation is no more technically challenging than for exon 51. We have designed molecular patches to target every dystrophin exon and based on research in our laboratory, some of the rarer mutations should be considered for testing because these are likely to be more responsive to exon skipping than some more commonly encountered deletions.

However, exon skipping will not be applicable for all Duchenne muscular dystrophy mutations. The dystrophin gene has some crucial pieces of code, particularly at the start and the end of the gene that are necessary to build a dystrophin protein that is able to perform its job of protecting muscle from damage. So, although it is technically possible to skip mutations in these crucial parts of the gene, important parts of the dystrophin protein may be lost. We are undertaking studies in mice at the moment to map which parts of the dystrophin gene are absolutely essential which will inform us more accurately about what is possible.

How soon other exons will be addressed will depend on how quickly safety, tolerability and a clear clinical benefit for skipping exon 51 can be conclusively demonstrated. The immediate future for exon skipping is likely to be frustrating for many people, but it is imperative that we don’t make any mistakes and safety and patient welfare is not compromised.

Professor Steve Wilton, MDEX consortium member, Australian

Neuromuscular Research Institute, Perth, Western Australia.

Q. I am a facioscapulohumeral

muscular dystrophy (FSHD) patient.

I read a news article about the molecular scalpel hope for Duchenne muscular dystrophy, in the newspaper and also online. Is this beneficial for FSHD patients?

Charley Chacko

A. The preliminary results of exon

skipping for Duchenne muscular dystrophy are encouraging, and indicate that this may be a potential therapy. Importantly, these trials show that muscle can be targeted by such therapies.

Duchenne muscular dystrophy is caused by mutations within a single gene that results in the encoded protein being non-functional. In FSHD however, the underlying cause is loss of repeated DNA units on the end of chromosome 4. Healthy individuals have many such repeats (up to ~150), whereas patients with FSHD generally have less than 11 repeats.

A current theory is that this reduction in repeat units instigates production of a protein that is not normally present in the muscle, which has deleterious effects. Therefore, in Duchenne muscular dystrophy an essential protein needs to be repaired, while in FSHD, a harmful protein needs to be inactivated. It should be possible to use a modification of the molecular scalpel technique to make the assembly of this harmful protein inefficient, and so hopefully improve muscle function.

As a first step, there are experiments currently underway in cells grown in the laboratory to test this theory.

Dr Peter Zammit, Kings College London. Dr Zammit is currently funded by the Muscular Dystrophy Campaign to research the role of muscle stem cells in FSHD.

Thinking ahead!

If you read the newspapers on July 25 you couldn’t possibly miss the news about the exon skipping trial carried out by British scientists with the American company AVI Biopharma.

It was good news – hopeful news – although we still have a long way to go until we understand the full potential of this new technology. However, new in this respect seems to be rather relative. Looking back at the research the charity has funded there were two scientific papers published in the early nineties reporting results of first exon skipping experiments. This is almost 20 years ago and it makes me feel proud that the Muscular Dystrophy Campaign supported the exon skipping pioneers.

We have been extremely successful in funding research at an early stage where no other support is available, and this will continue to be our role in the future. But we need to keep looking ahead as well. So, we also aim to help the scientific community to get ready for clinical trials. Although for some conditions this might still be some time away, we now need to ensure that everything is prepared for the day that promising technology is ready for testing in patients. This can be challenging especially in light of the rarity of the conditions. We need to ensure that information about people with a particular condition and who are willing to take part in clinical trials is centralised in a database – this is called a registry. Currently we are involved in setting up registries for myotonic dystrophy and facioscapulohumeral muscular dystrophy you will be able to read more about this in the next issue of Target Research. And secondly, we are helping the muscle centres in London and Newcastle with the administrative burden that comes with clinical studies by providing funding for clinical trial coordinators.

If you have any research questions please get in touch: t: 020 7803 4813 e: research@muscular-dystrophy.org

But without your fantastic help there might not have been this good news in the papers bringing new hope to our families. A big thank you to everybody who has made a donation and please keep supporting us so we can continue to bring more good news to you.

You can also join the discussion about research on TalkMD forum w: www.community.muscular-dystrophy.org

Dr Marita Pohlschmidt Director of Research, Muscular Dystrophy Campaign.

Links...

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In these harsh economic times, we’re working hard to save money. Now more than ever, we rely on every penny of your donations to fund vital research and provide support and care for people with muscular dystrophy and related conditions. With this in mind, we‘ve launched our new-look Target MD and Target Research – both to be delivered to you four times a year.

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