Target Research 2013 (2 of 4)

Target Research Issue 2 of 4 2013

How do we fund research?

Ensuring we fund the best quality science

Stem cell research and treatments

Why are stem cells special, and how could they be developed into treatments?

Clinical trials – a safety net

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

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Glossary This glossary is intended to help with some of the scientific and technical terms used in this magazine. Words that are in the glossary are highlighted in italics in the text.

About us

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.

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

Biobank – a place where researchers can securely store biological samples.

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.

Cell – The structural and functional unit of all known living organisms. They are often called the building bricks of life. Humans have an estimated 100 trillion cells.

Chromosome – cylindrical shaped bundles of DNA found in the cell nucleus. They consist of long, thread-like strands of DNA coiled up on themselves many times. We inherit 23 from our mother and 23 from our father.

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.

Drug screen – a way of testing many molecules (often several thousand) quickly, to test their potential to be used as a treatment for a disease.

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 causes the body to ignore or skip-over that part of the gene. This restores production of the dystrophin protein, albeit with a piece missing in the middle.

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

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.

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

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.

Nucleus – The control centre of a cell, which contains the cell’s chromosomal DNA. 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.

Placebo-controlled trial – a clinical trial where the effectiveness of a potential new drug is measured by comparing its effects to a placebo, or inactive drug.

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 – Ribonucleic acid, a substance very similar to DNA. When a gene is ‘switched on’, RNA carbon copies of the gene’s code are made. The RNA moves outside the nucleus where they direct the manufacture of proteins. DNA can be thought of as a recipe book in the library that you can’t take out.

RNA is a photocopy of a recipe that you can take home to cook something in your kitchen (making the protein).

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

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

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

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

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

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

www.muscular-dystrophy.org/research

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Welcome

Hello, and welcome to the second edition of Target Research of 2013.

In this issue we take a look into the exciting area of stem cell research. Our main article explains what stem cells do and how researchers are working towards developing stem cell therapies for people with muscular dystrophies and related neuromuscular conditions. I hope you like our cover picture – it shows a view down a microscope of stem cells developing into specialised muscle cells.

As a charity, it is our duty to invest the money our supporters raise, wisely. As such, we only fund the best quality research. Our second article in this issue explains how the Muscular Dystrophy Campaign chooses which research to fund. It describes how we select the best research projects to fund, and how our families help us make this choice.

The research team is always keen to get feedback about the information we send to you, so we’ve included a short survey (on page 9). This will help us to make make sure that Target Research is the magazine you want it to be.

I do hope you enjoy this edition of Target Research.

Neil Bennett Editor, Target Research t: 020 7803 4813 e: n.bennett@muscular-dystrophy.org tw: @NBennettMDC

Contents 4

Stem cell research and treatments update Why are stem cells special, and how could they be developed into treatments?

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Research news The latest news from the UK and around the world

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Our reader survey Let us know how we can improve Target Research

12 Funding research

How do we choose the best research?

15 Ask a Scientist

Your questions answered by UK researchers and clinicians 15 Clinical trials – a safety net

Dr Marita Pohlschmidt, the 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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Stem cells Stem cells are incredible cells with some amazing properties. Unlike most cells in our body, they can divide almost indefinitely and develop into many types of specialised cell. Only a few stem cells are necessary to create a new human being, they are the reason behind growth during childhood and they can repair injuries and damage to our bodies as adults.

With this ability to repair damage to our bodies, stem cells also offer real promise of longlasting treatments for human diseases. In this article we take a look at recent advances in stem cell research, and how these advances are being taken forward into clinical trials.

www.muscular-dystrophy.org/research

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O

Our bodies are made of around 100 trillion cells (that’s one hundred million

million!) and every second, around 50 million cells have to be replaced – because

of normal wear and tear or injury. But the specialised cells which make up our

tissues and organs have lost their ability to divide; and so the cells that need

replacement must be generated from other types of cells. These are called stem cells.

There are different types of stem cells – embryonic and adult stem cells dependent on where they are found. Embryonic stem cells are found in the early embryo and have the ability to The view down the microscope develop into any type of cell or tissue – such as blood cells, the brain or muscle. Adult stem Using powerful microscopes, researchers cells are found throughout the body and their ability to divide into the different types of cells are able to zoom in on cells grown in the laboratory. In this photo, stem cells can be is slightly restricted. Another characteristic of stem cells is that they can replace themselves. seen developing into specialised muscle cells When stem cells divide one of them will develop into a highly specialised cell, whilst the other and muscle fibres. Researchers have stained will replenish the pool of stem cells. (or dyed) different proteins in the cells Given their unique ability to repair and replace damaged tissue, stem cells offer great (so different colours are seen). This allows potential for treating diseases. Stem cells could one day be used instead of organ transplants – the process to be monitored more closely. it might be possible to grow organs from stem cells in the laboratory or to inject stem cells into a human body to repair or even replace damaged organs. However, until then much research remains to be done to understand how these cells are regulated and what triggers them to develop into a cell with a particular function. In this article we look at the most important stem cell types, the studies which are currently being undertaken and some of the challenges which need to be addressed before stem cells could be used as treatments.

Embryonic stem cells Embryonic stem cells, as their name suggests, are found in embryos at the very early stage of development. The cells have the remarkable ability to specialise into any type of cell which is technically described as pluripotency. In the embryo, just a few embryonic stem cells eventually give rise to every tissue and cell type in the entire body.

The ability to specialise into any tissue of the body means embryonic stem cells are used as an important tool in research. Researchers can isolate embryonic stem cells from embryos grown from eggs donated for research purposes and can use the cells to establish embryonic stem celllines. These cell lines can be grown almost indefinitely in the laboratory and are an ideal resource to study how stem cells are regulated and identify the factors that makes them develop into a specific cell type. When grown under certain conditions the cell-lines remain unspecialised, but by changing the composition of the cells’ food or by turning on specific genes researchers can already develop embryonic How are embryonic stem cells made? stem cells into a number of Embryo (blastocyst) specialised cell types. It is, for example, already possible to produce muscle cells and researchers are currently using Embryonic stem cells embryonic stem cell lines to are isolated from an study the different stages the Embryo (blastocyst) embryo five – seven cells pass through as they days after the egg develop into functional is fertilised muscle cells.

Clinicians hope that Embryonic stem cells Embryonic stem cells embryonic stem cells could The stem cells can one day be used to treat develop into a range of cell types in the human diseases including laboratory. muscular dystrophy and related neuromuscular conditions.

However, since embryonic stem cells can develop into any type of tissue there is a risk that injecting the cells into Nerve cells Muscle cells Kidney cells an individual could lead to leading the way forward Nerve cells

Muscle cells

Kidney cells

6 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.

In the field of neuromuscular diseases embryonic stem cells can also used to study the impact of genetic mutations on muscle or nerve function. The mutations can be introduced into the DNA of a generic embryonic cell line growing in the laboratory. Alternatively cell lines can be established directly from embryos donated by families who have undergone pre-implantation genetic testing and already carry a mutation in a disease gene. These cell-lines can also be used to produce large numbers of muscle or nerve cells which are used for large drug screens to identify drugs or molecules which may have the potential to treat the condition.

Adult stem cells Adult stem cells are found in all tissues throughout our body. Compared to embryonic stem cells, they are slightly more specialised and, can only develop into a limited number of cell types. Adult stem cells that are associated with muscle cells are called satellite cells. In healthy muscle they are in a dormant or “sleeping� state and sit along the edges of the muscle fibres. When the muscle is damaged or injured the cells are activated and move along the muscle fibres to find the damaged area. They then divide and fuse with muscle cells to repair the damage or specialise into new functional muscle cells to replace muscle that is beyond repair.

Satellite cells are the main focus of stem cell research, since it is believed that they offer great potential for development into a treatment for muscular dystrophy and related neuromuscular conditions. However, satellite cells do not survive for a long time outside the body and therefore it is difficult at the moment to grow sufficient satellite cells to consider this as an option for a therapy. Secondly, it would be difficult to treat every muscle in the body using satellite cells since a method has not yet been found how to use the blood as a delivery route. They would have to be injected into each individual muscle.

It is also known that satellite cells in dystrophic muscle are less able to repair the muscle than those in healthy muscle. It is not yet clear why this is the case, but if the muscle environment plays a role then transplanting healthy satellite cells into a patient with a muscular dystrophy may not result in efficient muscle repair.

The challenges of using satellite cells as a potential therapy have lead researchers to investigate other adult stem cells for their potential to treat muscle disease. Of particular interest are stem cells called mesoangioblasts which are found in the walls of blood vessels. They have the ability to develop into muscle cells and, unlike satellite cells, mesoangioblasts can be grown in the laboratory. They also travel well through the blood stream and pass the barrier to reach the muscles. When tested in animal models of Duchenne muscular dystrophy it has been shown that they are able to restore dystrophin production and improve muscle function.

Satellite cells maturing into muscle cells in the laboratory. www.muscular-dystrophy.org/research

Stem cell clinical trials Recently, clinicians in Italy tested for the first time the use of mesioangioblasts to treat boys with Duchenne muscular dystrophy. The mesioangioblasts were isolated from healthy individuals and injected into the bloodstream of six boys with Duchenne muscular dystrophy. The main focus of the trial was to test the safety of the procedure, but a potential improvement in muscle function was also measured.

The results of the trial are expected later this year.

In the USA, trials are underway testing whether blood stem cells (called haematopoietic stem cells) can safely be given to people with myasthenia gravis or idiopathic inflammatory myopathies. These are acquired, autoimmune conditions and researchers hope the stem cells will replace the white blood cells which attack healthy mucsle cells in affected people. Although testing whether the treatment is safe is the priority, the clinical trial will also assess potential benefits for disease progression.

It is important to note that there are currently no licensed stem cell treatments for muscular dystrophies or related neuromuscular conditions.

There are clinics that offer stem cell treatments using a cocktail of cells of often dubious origin. The safety and benefit of these potential treatments has not been tested in clinical trial.

This means the treatment may be ineffective and even dangerous.

Recently a woman in the USA who received stem cells as a cosmetic treatment was left with bone fragments instead of new skin in her eyelids. In this case the injected stem cells specialised into the wrong type of tissue and this could have caused serious harm. Luckily, surgeons were able to remove the fragments and no lasting damage was done.

For more information about clinical trials as they start, please look at our clinical trials database at www.muscular-dystrophy.org/ research/clinical_trials.

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Stem cell research we are funding: Does disturbed satellite cell function contribute to facioscapulohumeral muscular dystrophy?

Work in Prof. Peter Zammit’s laboratory is currently exploring the role that satellite cells have in the progression of facioscapulohumeral muscular dystrophy (FSH).

Here we find out more about the project from PhD student Louise Moyle: My PhD project is investigating how adult muscle stem cells (satellite cells) are affected in FSH muscular dystrophy. This form of muscular dystrophy occurs when a section of DNA called the D4Z4 region on chromosome four is shortened. This region of DNA consists of repeated units; typically, healthy individuals have at least 11 repeat units, whilst people with FSH muscular dystrophy have fewer - with between one and ten repeats. Deletion of these repeats allows a gene called DUX4 to be made into a protein. DUX4 is not usually produced in muscle cells, and when the protein is produced in satellite cells it can prevent the stem cells specialising into muscle. Since the role of satellite cells is to repair muscle damage, if stem cells can’t function properly due to production of DUX4, muscle damage could go un-repaired and the muscle weaken.

To improve our understanding of the effects of DUX4 production in the satellite cells of people with FSHD, we use a model system where DUX4 is delivered into mouse satellite cells grown in the laboratory. We know that the effects seen in mouse satellite cells are similar to those in human cells, which makes the model a good system for studying the disease.

DUX4 is a type of protein called a ‘transcription factor’. This means it can alter how other genes are read – either turning

them on or off. Some of the genes altered, in turn alter other genes, and this can lead to a “domino effect”, with many genes and biological pathways being altered. We used our model system to determine which genes were turned on or off in satellite cells when DUX4 was present. This highlighted the crucial biological pathways and genes which were altered by DUX4.

We are now looking in more detail at the effects of several biological pathways, one of which has never been studied in mammalian muscle before, although it is important in stem cells from other parts of the body. As well as characterising the function of these novel DUX4-effected genes we are developing methods to specifically block the pathways which DUX4 activates. By blocking one pathway at a time we can see which are most harmful to the satellite cell; this may help researchers to choose drug targets in the future. Importantly, since drugs are already available which target some of these pathways, it may be possible to use existing drugs as an alternative to making a drug which could directly block the DUX4 protein.

Although we are a long way from clinical trials, it is important to understand how DUX4 production in satellite cells and muscle cells causes the clinical features of FSHD. The more we know about the underlying processes which cause the condition, the more approaches will be available for the development of potential treatments in the future.

Satellite cells maturing into muscle cells in the laboratory. leading the way forward

News 8

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.

Study of long-term steroid use in boys with Duchenne muscular dystrophy A group of researchers led by Prof. Francesco Muntoni has published the results of a study into steroid use in boys with Duchenne muscular dystrophy. The researchers used data collected by the NorthStar database to evaluate the effectiveness and side-effects of giving prednisolone in different ways. This could help clinicians to improve and to harmonise care in different hospitals.

Boys with Duchenne muscular dystrophy have been treated with steroids for almost 20 years, and steroids are the only drugs which can keep boys walking for longer. In the UK most boys are treated with a steroid called prednisolone, but there has never been a clinical trial to test the best way of giving the steroids.

A team of researchers and clinicians from around the UK has used the natural history data held in the NorthStar database (see box) to investigate the long-term effects of steroid use. The database includes information about the medicines and treatments given to individual boys, along with details of their condition and symptoms.

The researchers examined the benefits and side-effects that boys experienced when they were given prednisolone in different ways – either every day or intermittently (10 days on/10 days off ). Both groups of boys showed a decline in their walking ability from the age of seven, but boys who were given steroids every day declined more slowly and walked until they were, on average, 14.5 years old (compared to 12 years in boys who took the steroids intermittently). However, boys who received steroids every day were more likely to experience side-effects including increased weight and high blood pressure.

The authors of the paper did not say which was the best way to give steroids.

However, they said that the study will increase understanding about long-term steroid use in boys with Duchenne muscular dystrophy. This information about effectiveness and side-effects may help clinicians to improve care and could help families and boys make more informed choices about steroid use and how to take the drugs. At the moment, choice of steroid and dose varies between hospitals and individual clinicians, and this data might help to harmonise care across the country.

The study is the largest of its type ever performed – using natural history data from 396 boys with Duchenne muscular dystrophy taking steroids. Although this kind of natural history study provides clinicians with useful information, the only way for researchers to test steroids properly is in a clinical trial. This would ensure that all participants were assessed in exactly the same way and researchers in Newcastle are now working towards this aim. www.muscular-dystrophy.org/research

THE NORTHSTAR DATABASE The Muscular Dystrophy Campaign gives funding support to the UK National Neuromuscular Database. The database was initially developed as part of the Muscular Dystrophy Campaign-funded NorthStar project.

It was set up by Professor Francesco Muntoni and Dr Adnan Manzur to collect natural history data from boys with Duchenne muscular dystrophy who are still walking.

The data held in the database is collected from a large number of muscle clinics across the UK. This enables clinicians to compare how people are treated in different clinics which helps to harmonise care in different hospitals. Natural history data also helps clinicians put people with a single condition into different subgroups. This improves understanding of how the disease progresses and means more detailed information can be given to families. A better understanding of disease progression can also help clinicians to design clinical trials in the future and help them to measure the effects of potential new drugs through these trials.

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AllTrials petition The Muscular Dystrophy Campaign has signed a petition being orchestrated by a group of organisations including the British Medical Journal and Sense about Science. The petition – called Alltrials – is calling for all clinical trials to be registered and the results published, whether positive or negative.

The design of clinical trials relies on the use of previous results. Publication of all clinical trials – whether the results are positive or negative – should be treated with equal importance since these could all have the potential to improve trial design, avoid duplication and increase transparency.

Currently, the organisers of clinical trials do not have to release all the trial results they have about a potential drug. If as much information as possible about potential treatments were released, it could help clinicians and people affected by neuromuscular conditions understand potential side-effects and let them make

informed choices about their treatment options.

Our full response to the petition said: “The Muscular Dystrophy Campaign is pleased to support the AllTrials petition calling for all clinical trials to be registered and results to be published.

“As a medical research charity, our supporters rightly have an expectation that the funds they raise will be used to move potential new treatments into clinical trials and the clinic as quickly and efficiently as possible.

Encouraging groups performing clinical trials to publish the results could speed up this process and

give our families faster access to potential new treatments.

“We are aware that scientific journals focus on publishing positive results and companies may have various reasons for not publishing all clinical trial results. However, since a key part of clinical studies and trials is using previous results to improve study design, we believe all clinical trials – whether the results are positive or negative – should be treated with equal importance.

The publication of all clinical trial results could improve trial design, avoid duplication and increase transparency.”

Feedback We’re always keen to get feedback about how we communicate research to you. If you’d like to help us to improve Target Research and to bring you the research news you want to read, please fill in this short survey and send it to us at the address shown on page 10.

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leading the way forward

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PTC ANNOUNCE ATALUREN TRIAL DESIGN In the last issue of Target Research, we reported on PTC Therapeutic’s application for conditional approval of ataluren. This drug has the potential to treat nonsense mutations in boys with Duchenne muscular dystrophy.

The decision about whether to grant conditional approval rests with the European Medicines Agency and approval could lead to ataluren being marketed in the EU. However, if conditional approval is granted, PTC Therapeutics will still be required to conduct a Phase III placebo-controlled trial to confirm their previous results.

The company has now announced details of the Phase III trial. It will be a global trial and will include at least one trial centre in the UK. Researchers aim to recruit 220 boys and enrolment is scheduled to start in the first half of this year. Participants in the trial will receive either ataluren or a placebo (an inactive drug) and the trial will test the dose of ataluren which showed most potential in the previous trials.

Participants will visit the study centre every eight weeks for 48 weeks, and the effectiveness of the treatment will be measured using the six-minute walk test and other measures of muscle function and quality of life.

When we receive more details of the trial, we will publish them in our online clinical trial database at www.musculardystrophy.org/research/clinical_trials where you can also find more information about taking part in clinical trials.

Feedback

New mouse model of intermediate spinal muscular atrophy Mouse models are a strain or breed of mouse which have a disease that is similar to a human disorder. There are already several mouse models of spinal muscular atrophy, with mutations that cause symptoms similar to spinal muscular atrophy in humans. However, many of the existing mouse models of SMA are models of the most severe forms of the disease – with the mice usually surviving for only two to three weeks.

Scientists from Columbia and California in the USA have used genetic engineering to produce a mouse model of SMA which has less severe disease. The newly-developed mouse model shows increased strength, muscle function and has lived for longer than the models currently in use and scientists believe they may be useful to learn about how effective exon skipping technology might be in treating people with spinal muscular atrophy. The increased lifespan of the mice may also help researchers discover drugs with the potential to treat spinal muscular atrophy.

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

continued

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Using exon skipping technology in a model system of Ullrich congenital muscular dystrophy A group of scientists from Italy has used exon skipping technology to restore the production of a protein called collagen VI in a model system of Ullrich congenital muscular dystrophy. Collagen VI is a protein produced by our muscle cells which is transported to the outside of the cells where it forms a mesh that surrounds the muscle cells and supports their structure. Mutations in the genes that carry the instructions for the collagen VI protein can stop the protein assembling into the correct shape which can disrupt the mesh of collagen VI which usually forms around the muscle cells. This can lead to Ullrich congenital muscular dystrophy.

Usually, everyone inherits two copies of every gene – one copy from each parent.

Some cases of Ullrich congenital muscular dystrophy are caused by a mutation in one of the copies of the collagen VI genes (this is called autosomal dominant inheritance). Scientists believe the collagen VI protein is produced from the mutated gene as normal, but when it is built into the mesh outside the muscle cells it forms the wrong structure. This disrupts the structure and leads to wasting of the muscles.

Healthy individual

Individual with Ullrich congenital muscular dystrophy

Collagen VI from mutated gene

Collagen VI Muscle cell

A mutation in one copy of the collagen VI gene stops the formation of an ordered mesh of protein.

Collagen VI protein (shown as lines here) is produced from Exon skipping technology is used to block both copies of the collagen VI gene (different colours). production of protein from the mutated gene.

The protein forms an ordered mesh around the muscle cells.

Collagen VI is only produced from the healthy copy of the gene and the ordered mesh of collagen VI around the muscle cells is restored.

The researchers designed molecular patches that bound to the mutated gene and stopped it being made into a protein. The healthy copy of the gene could still be read and made into a protein as normal. When the cells with the mutated collagen VI gene were grown in the laboratory, there was no mesh of collagen VI. When the molecular patches were added to the cells, the collagen VI produced by the cells could form the ordered mesh seen around healthy cells.

This study provides proof of principle that exon skipping technology may have the potential to be developed to treat some forms of Ullrich congenital muscular dystrophy. It must also be noted that exon skipping technology will only be able to treat a very small minority of people with a certain type of mutation – other potential treatments will need to be developed for most people with the condition.

However, the research is in the very early stages, using cells grown in the laboratory.

Before the technology could be tested in clinical trials, researchers will need to carry out further tests in animal models to confirm the results and to improve and optimise the technology.

Hello from Target MD Greetings to you from the team that puts together Target MD, the charity’s lifestyle magazine.

In our second edition of the magazine for 2013, we focus on care and caring. We meet a young carer, Alaina, who cares for her mum and older sister; we meet Val and Mark, who talk about what happens when marriage and caring become entwined; we bring you information about the Carer’s Allowance, about the NeuroMuscular Centre in Cheshire that offers vital support for carers and a glimpse into life at the Helen & Douglas House in Oxford that provides respite care for families.

We also tell you about the hugely successful Make Today Count campaign that saw 130 daredevils skydiving at sites across the UK, a flashmob event in Glasgow, bucket collections, dress-down days and cake sales, not to mention a vibrant Asian banquet in Bristol. The colourful photo spread in Target MD will give you an idea of just how orange the UK became on Friday 1 and Saturday 2 March, and how our fabulous supporters raised £80k for research into Duchenne muscular dystrophy.

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

I’d love to hear from you.

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

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Peer review QUALITY CONTROL FOR SCIENCE Dr Julia Ambler, Head of Grants at the Muscular Dystrophy Campaign, explains how the charity chooses which research to fund.

www.muscular-dystrophy.org/research

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Selection process for research proposals For over 50 years the Muscular Dystrophy Campaign has been funding world-class, pioneering research into potential treatments and cures for people with muscular dystrophy and related neuromuscular conditions, from basic science and translational research to clinical pilot studies.

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n that time, the charity has contributed to crucial scientific breakthroughs.

The charity laid the foundations for the promising technology of ‘exon skipping’ which is currently being tested in clinical trials for boys with Duchenne muscular dystrophy. It also funded work that has led to the development of new, promising IVF technology that may prevent mitochondrial myopathy being passed to future generations. This is now close to clinical trial.

At the heart of our research programme is our commitment to ensure that all the research we fund is of the best possible quality. We have a duty to ensure that the money our families and supporters have put time and energy into raising for us is invested into research that has the best chance of succeeding and providing a benefit for them in the future.

What is peer review and why is it important?

Peer review is used by research funders to assess the quality of scientific ideas by subjecting them to independent scrutiny by qualified experts (peers). Funders use peer review when choosing what research to fund and scientific journals use it when deciding whether a research paper is worth publishing.

As a member of the Association of Medical Research Charities (AMRC), the Muscular Dystrophy Campaign is required to use peer review to ensure that the research we fund is of good quality.

The Muscular Dystrophy Campaign is dedicated to improving the lives of all children and adults affected by muscle-wasting conditions. We fund research into more than 60 neuromuscular conditions and, through a rigorous international peer review, we ensure that only the best research is funded. Here’s the process a research grant application goes through.

Research grant application

Lay application

Scientific application

Lay Research Panel The Lay Research Panel is comprised of individuals affected by a muscle-wasting condition, an occupational therapist and a physiotherapist. We also have a scientific advisor at all lay panel meetings who does not have voting rights but answers any scientific questions the panel may have.

International peer review

Peer review tells us if the research is: n

scientifically valid, significant and original

n

timely and achievable

n

unnecessarily duplicating other work

n

using appropriate methodologies

n

carried out by researchers with the right skills and facilities

n

value for money.

Medical Research Committe The committee members include a selection of renowned researchers, clinicians and representatives from the lay panel. The chair is a Trustee of the Muscular Dystrophy Campaign.

Peer reviewing a piece of research provides a quality assurance. It tells you that the research will be conducted and presented to a standard that other scientists accept.

Board of Trustees meeting leading the way forward This is the final stage of a grant applicaton process, where a decision is made.

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THE GOLD STANDARD The AMRC audits their members every five years to ensure that we are using the system correctly and adhering to the high standards they have set.

The AMRC has five guiding principles of peer review which we must use:

Accountability – our processes and criteria must be transparent

Balance – applications must be reviewed appropriately for their requested value and committees are made up of scientists with a range of expertise and experience Independence – awards should be made by impartial individuals and neither charity staff nor Trustees should have undue influence over the process Rotation – members of internal review panels should be changed regularly to minimise bias and to allow new ideas and techniques to be brought in as science develops Impartiality – conflicts of interest must be managed to ensure impartiality is maintained.

How we fund research All the research grants that we fund go through a rigorous selection process to ensure we are funding the best quality science and that the projects are relevant for people with a muscular dystrophy or related neuromuscular condition. We have a competitive annual grant round during which applications are ranked after they have been peer reviewed. The ability to compare applications with each other gives our scientific panel, the Medical Research Committee, a tool to evaluate the projects more precisely and to better reach a consensus about the research that warrants funding.

Any researcher who would like to apply for a grant from us must fill in both a scientific application and a lay application. The scientific application is a detailed description of the project and all of its related costs as well as any ethical considerations, such as the use of animals or human samples. The lay application contains a less detailed proposal, and is written in lay (straightforward, easy-tounderstand) English and goes to our Lay Research Panel, which consists of people who are affected either directly, or indirectly, by a muscle-wasting condition. The lay application consists of questions that the Lay Research Panel feel are the most appropriate for helping them to prioritise the projects. The Panel discusses each application and provides written feedback for the Medical Research Committee.

The scientific applications go out to peer reviewers all over the world, who are experts in a variety of specialised areas of science related to the field of muscular dystrophy and related neuromuscular conditions. They provide a detailed and objective critique of whether the project appears to be worthwhile, whether it is achievable and if there are any weaknesses that should be addressed in the experimental design. The purpose of the peer review is two-fold: firstly it ensures that we, the charity, and our Medical Research Committee gain an objective view about the scientific viability of a project and secondly, it provides the applicants with constructive feedback on the proposed project.

Our Medical Research Committee considers and discusses all of the information – application, reviewers’ reports, applicant’s response to reviews and feedback from the Lay Research Panel - before making a recommendation to the Board of Trustees about which projects should be funded. Two members of the Lay Research Panel also sit on the Medical Research Committee and will vote on the funding decisions. This dialogue between scientists and lay people ensures that the research is not only good quality science but is also relevant to the people we support.

Monitoring our research Once an award has been made, grantees are required to submit an annual report which, if satisfactory, will release the next year of their funding. These reports are monitored by our Medical Research Committee to ensure that the project is progressing well and meeting its original objectives.

Should there be any problems, these can be dealt with in a timely manner.

Science is not always straightforward and sometimes changes need to be made to the original plan. These modifications are considered and monitored by the Committee to make sure that the new plan is of the same high standard as the original application. www.muscular-dystrophy.org/research

GET INVOLVED! As the experts on their own conditions, we believe that families and supporters can provide us with help in prioritising what research to fund as well as how to communicate that research to a wider audience. If you want to get involved, you can “dip your toes” into research by joining our Talk Research group: a committee of supporters who are keen to have a say in how we communicate research. Their feedback on our print and web-based research communications service has proven invaluable!

To find out more please contact us on 020 7803 4813 or research@muscular-dystrophy.org

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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.

Q

In 2004, when she was 14 years old, my daughter was diagnosed with McArdle disease at the Children’s Hospital in New Orleans. Today she is 23 years old, and she is pregnant. Will she be at high risk during pregnancy because of her condition?

Amanda Jones

A

The group of people we study includes over 100 people with genetically confirmed McArdle disease. In this group, there were 57 pregnancies reported (including two twin pregnancies), in 33 women. Most of these reports were retrospective – so made after the pregnancy had happened – because the vast majority of women in the study group were not diagnosed until much later in life.

Most of the women with McArdle disease reported feeling better during pregnancy and none reported feeling any worse. None of the women, or their babies, suffered any harm during the birth. One woman noticed dark urine following one of her labours, but there were no other reports to suggest that acute rhabdomyolysis happened during or after labour. The rate of assisted labour (the use of forceps, vacuum device, or caesarean section) in people with McArdle disease was no different from that in the general population and all of the babies born to

women in the group were healthy.

McArdle disease is inherited in an autosomal recessive way. This means that an individual must inherit two mutations – one from each parent.

This means the risk to the baby of having McArdle disease is usually very low, unless the parents are related to one another, or come from a small isolated community.

Looking after infants when the mother has McArdle disease can cause specific issues. When breast feeding, mothers must remember to support their arms – using the arm of a chair or pillow. When walking and carrying the baby be careful, and swap arms if you become uncomfortable. Don’t try to carry the baby long distances – for example don’t park the car too far away from the house – and carrying the baby close to the chest may be easier than carrying them in a car seat.

Be careful carrying a pram or buggy up steps or stairs, and always ask for help if you need it. If available, applying for a disabled parking badge might help to save you walking long distances with heavy prams. Finally, toddlers tend to run off and parents with McArdle disease can’t run! As such, affected parents should use a wrist or chest strap to prevent the toddler from running away.

Dr Ros Quinlivan

Consultant Neurologist, National Hospital for Neurology and Neurosurgery

Clinical trials – A safety net News reached my desk this week that the Italian Government has sanctioned a controversial stem cell treatment, despite a lack of any scientific evidence demonstrating it is safe and effective.

The decision followed an extensive media campaign and is supported by a number of patient groups. Scientists all over the world are horrified that Stamina Foundation, the company behind this technology is allowed to legally give this treatment to 32 children with life-limiting conditions.

As a patient organisation, we understand the urgency felt by families and individuals affected by incurable conditions for a treatment to become available. It is our responsibility to remind the scientific community, regulators and health care providers of this urgency. Yet it is also our responsibility to protect vulnerable families from treatments that are not only unproven and expensive, but also considered potentially dangerous by the scientific community.

Regulators in this country approve drugs or treatments only on the basis that effectiveness and safety can be demonstrated in a controlled study – a clinical trial. Our charity fully backs this approach. Although we campaign hard to make the processes around delivering treatments faster and more efficient, we would never recommend something that could put the lives of the people we support at risk.

The good news is that a number of clinical trials are currently on the way, testing promising technologies for various neuromuscular conditions. I feel confident to say that first treatments might now be on the horizon. We will fight to ensure that everybody eligible is guaranteed access to treatments that reach the clinic – and that these are robust, effective and safe.

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

Target MD and Target Research

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 neuromuscular conditions. With this in mind, we‘re inviting you to subscribe to Target MD and Target Research – both to be delivered to you four times a year.

That’s right! You will receive Target MD four times a year along with Target Research.

And all for an annual subscription gift of just £18. This will help us cover our costs – even reduce them – while ensuring the same editorial quality you’d expect from every issue of Target MD and Target Research. And because they now only go to people like you who really want to read them, and they’re both now produced fully in-house, the Muscular Dystrophy Campaign can free up more funds to spend on further research, campaigning, support and equipment grants.

If you’d like to subscribe to the magazines, please post your details, together with a cheque for £18 made payable to ‘Muscular Dystrophy Campaign’ to Target MD Subscriptions at 61 Southwark Street, London SE1 0HL: I wish to subscribe to Target MD and Target Research for one year, at a cost of £18.

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