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Inherited muscle-wasting conditions affect approximately 1 in 1000 people, and to date, there are upwards of 50 discrete diseases, each of which is defined by a distinct genetic mutation. Patients commonly present with progressive muscle weakness but the severity and complications vary dramatically between the different diseases.

Research at the Wolfson Centre for Inherited Neuromuscular Disease is focused on some of the most severe and devastating muscle-wasting diseases including muscular dystrophies, and the childhood form of motor neuron disease, spinal muscular atrophy. The clinical research team are actively engaged in several pioneering clinical trials and studies involving patients at RJAH and further afield. The internationally-recognised laboratory team, meanwhile, work to find new ways to diagnose and treat inherited neuromuscular diseases. By designing and developing highly specialised research tools and combining these with the use of cutting edge “omics” technology, their research aims to unravel the complexities of disease mechanisms and identify new targets for therapy development.

The laboratory team work closely with the clinical team so that scientific advancements can benefit patients as quickly as possible. As a group, they are highly committed to training the next generation of scientists and doctors at RJAH, and work closely with affiliated Universities at Keele, Manchester and Chester, to deliver this.

The Clinical Research Team: Prof Tracey Willis, Dr Richa Kulshrestha, Mr Nigel Kiely, Dr Yvette Easthope-Mowatt, Mr Nick Emery, Mrs Claire Bassie, Mrs Kerry Jones, Mrs Jenny Moustakas

The Laboratory Research Team: Prof. Caroline Sewry, Prof. Glenn Morris, Dr. Heidi Fuller, Dr Ian Holt, Dr Le Thanh Lam, Dr Sharon Owen, Darija Šoltić, Emily Storey Affiliate member: Dr Melissa Bowerman (Keele)

Funded by the Orthopaedic Institute Ltd

The Muscle Team has successfully retained its status as a ‘Centre of Clinical Excellence’ for paediatric and adult patients, an award given by the Muscular Dystophy UK (MDUK) Charity at a ceremony on 15th September 2019. MDUK reviews the centres providing neuromuscular care every three years.

Tracey Willis has been appointed by Chester University as Professor of Paediatric Neurology and recognized by RJAH as “Best Individual Achiever, 2018”.

The Muscle Team won a Meridian “Celebration of Innovation” award for embracing genomic medicine and the potential of 100,000 Genomes Project to transform the way health is delivered in rare disorders.

The Muscle Team has successfully retained its status as a ‘Centre of Clinical Excellence’ for paediatric and adult patients, an award given by the Muscular Dystophy UK (MDUK) Charity at a ceremony on 15th September 2019. MDUK reviews the centres providing neuromuscular care every three years.

Tracey Willis has been appointed by Chester University as Professor of Paediatric Neurology and recognized by RJAH as “Best Individual Achiever, 2018”.

The Muscle Team won a Meridian “Celebration of Innovation” award for embracing genomic medicine and the potential of 100,000 Genomes Project to transform the way health is delivered in rare disorders.

RJAH “Best Individual Achiever” and Meridian “Celebration of Innovation” Awards
The Laboratory Research Team welcomed two new members, Dr Sharon Owen and Emily Storey, both working with Dr Heidi Fuller on new projects. Sharon is working on a Spinal Muscular Atrophy project funded by Sparks and Great Ormond Street Hospital while Emily Storey is a Keele PhD student working on congenital muscular dystrophy. Dr Fuller was promoted to Senior Lecturer at Keele University and has joined the editorial boards of both “PLOS ONE” and “Scientific Reports”.

Dr Heidi Fuller and Dr Sharon Owen presented their research into identifying treatment strategies for children with spinal muscular atrophy (SMA) at the launch event of No Time to Lose, a campaign by children’s medical research charity Sparks. This charity fundraising event in London was hosted by its patron, Gabby Logan.

Dr Owen and Dr Fuller at the “No Time to Lose” launch event in London

Clinical Research Projects

The Muscle Team has participated in multicentre studies of the natural history of SMA (SMA Reach project) and the genetics of Duchenne muscular dystrophy.

The Muscle Team has successfully recruited patients to two pharmaceutical trials: SIDEROS, a placebo-controlled trial with idebenone, targeting mitochondrial function in Duchenne muscular dystrophy, and ITALFARMECO, another placebo-controlled trial aiming to reduce fibrosis in dystrophic muscle. It has also successfully completed a pilot study of arm cycling in patients with facioscapulohumeral dystrophy.

The results were presented at UK Neuromuscular Translational Research conference in Newcastle-upon-Tyne. Funding is secured for another study in this patient group to study biomarkers and their variation with exercise.


Spinal Muscular Atrophy

During the last two years, treatment of SMA has been greatly advanced by availability of Nusinersen, an intrathecal treatment, for patients with severe SMA type 1 through Managing Access Program. The Clinical Team has been the main hub in collaboration with University Hospital of North Midlands in the West Midlands region for delivering this complex treatment. The recent approval of this drug by NICE and NHS England will now allow for the treatment to be accessed by less severe SMA type 2 and type 3 patients.

SMA is the most common genetic cause of death in infants in the UK, and it is estimated that there are approximately 2,000 – 2,500 children and adults living with the condition in the UK. Although recent research has led to breakthroughs in the treatment of SMA type 1, it is not clear whether the underlying causes of this type are shared by other types of SMA. In the new Sparks research project, led by Dr Heidi Fuller, Dr Owen will study the biology of the different types of SMA and identify new drugs that could help to treat those children.

Darija Soltic gave an oral presentation of her work at the annual “Cure SMA” Congress, held in July this year in Anaheim, California, and work based on her Ph.D. thesis has been accepted for publication in “Human Molecular Genetics”. Dr Fuller chaired a session at the UK SMA Research Conference at Keele University in January, 2019.


The MDA Monoclonal Antibody Resource

Monoclonal antibodies produced by CIND are made freely available internationally and the cell lines that produce them have been given a safe and permanent home in the Developmental Studies Hybridoma Bank (University of Iowa). However, Dr Le Thanh Lam is continuing to respond to antibody requests from academic researchers worldwide. These mAbs have played a major role worldwide in clinical trials of new treatments for the muscular dystrophies.

Prof Morris was a co-author on “Report of a TREAT-NMD/World Duchenne Organisation Meeting on Dystrophin Quantification Methodology” published in Neuromuscular Disorders in June 2019.


Nemaline Myopathy

Nebulin is a very large (600-900kDa) protein of the muscle contractile system and genetic mutations are a major cause of the inherited mobility disorder, nemaline myopathy. There are two forms of nebulin, one containing “exon 143 protein” and another in which this is replaced by “exon 144 protein”. We used new monoclonal antibodies, specific for 143 or 144, to show that 144 is the isoform present in cultured muscle precursors.

Our collaborative work with the University of Helsinki was supported by the Orthopaedic Institute and has now been published in Scientific Reports. In a new project (2018-2020) supported by the Orthopaedic Institute, we are seeking to identify proteins that bind to nebulin isoforms with either exon 143 or exon 144. A protein called KHLH40 seemed a likely candidate because human mutations in KHLH40 can also cause nemaline myopathy. However we found that both nebulin isoforms, when attached to beads, showed equal binding to KHLH40 in human muscle or myotube extracts. Other candidates are being investigated.


Nesprins and Emery-Dreifuss muscular dystrophy

Nesprins (nuclear envelope spectrin-repeat proteins) encoded by the SYNE1 and SYNE2 genes, are involved in localization of nuclei. The short isoform, nesprin-1-alpha2, is required for relocation of nuclei during muscle development. Using specific antibodies in a study supported by the British Heart Foundation, we have now shown directly that both nesprin-1-alpha2 and nesprin-1-giant co-localise with kinesin in human muscle cell cultures. In adult muscle, nesprin-1-alpha2 was found, together with kinesin, only on nuclei associated with neuromuscular junctions. In heart, it was found only in the cardiomyocyte nuclei involved in cardiac function.

These studies help us to understand how mutations in several different genes (emerin, lamin A, SUN and nesprin-1) can all cause Emery-Dreifuss Muscular Dystrophy. This work has been submitted for publication and was presented at the 9th UK Nuclear Envelope and Chromatin Organization Meeting and 2nd International Meeting on Laminopathies held in London, Sep 3rd-5th, 2019.

Popeye Proteins and Cardiac Conduction

Dr Ian Holt has continued to develop and characterize new monoclonal antibodies (mAbs) against Popeye (POPDC) proteins for a collaborative project with Thomas Brand of the National Heart and Lung Institute (London) funded by the British Heart Foundation. Mutations in Popeye proteins can cause a form of limb-girdle muscular dystrophy with conduction defects, similar to Emery-Dreifuss muscular dystrophy.

Mice lacking Popeye proteins have cardiac conduction defects that mimic “sick sinus syndrome” in humans, a disorder that requires a pacemaker to be fitted. We have now shown an interaction of both POPDC1 and POPDC2 with both cardiac actin and XIRP1 (Xin actin-binding repeat protein 1), a protein known to be associated with heart pathology and cardiac conduction defects.

POPDC2 (green) and XIRP1 (red) are both found at intercalated disks (arrow) and at actin bands of muscle fibres in the heart



Clinical Activity

ORLAU is a busy department and there has been plenty going on this year. We continue to see a steady stream of patients for analysis of their movement or supply of assistive devices and orthotics. Over the years we have built up a reputation for helping patients to walk better, which inevitably means studying legs. More recently our upper limb service has been growing and we hope to expand the number of clinics in the future so we can help more adults with their arm function. We are continuing to develop our gait analysis services too and saw our first amputee patient recently, working with the Artificial Limb and Appliance Service (ALAC) at Wrexham.

Our rehabilitation engineering team have also been busy, developing and testing new designs to improve our patient devices. The team also look after ORLAU’s services in the community. Matthew Hardy has been busy running our Community Standing Frame Service, having taken over from Graham Richards in the Summer of 2018. We have also introduced new digital technology to our transportable gait laboratory.

All this clinical work feeds into our research plans for the future.

Locomotor assessment sensors

Research is vital to the team


We are very keen to pass on our expertise and learning to others and this work has continued over the last year. As a department we support national training initiatives for physiotherapists and clinical scientists. We have also put a bespoke course together for Matthew Hardy to support his new role in the community.
Individual members of staff are involved in teaching nationally and internationally but in 2018 we came together to run our first gait analysis course in some years. The course was organised by Sarah Jarvis under the umbrella of the Orthopaedic Institute and we received excellent feedback from our delegates. The same course ran again in June 2019 and we are planning a new course, in contracture management, for the Autumn, led by engineer Keith Miller and physiotherapist Will Bromwich.

ORLAU technical staff have been developing their expertise in writing computer code over the last year. Early in 2019 we were awarded a grant by CMAS (the gait analysis society covering the UK and Ireland). The grant has allowed us to set up a national programme for sharing and learning coding, aimed at staff working in gait labs. That programme is being run by Dimitra Blana, a collaborator of ours from Keele University.

Movement Analysis

In January 2019 we welcomed Dr Raphael Gross to ORLAU.  Raphael is a rehabilitation doctor from Nantes in France and he joined us for a 6 month fellowship to study muscle co-ordination in the upper limb.  His costs were covered by the Orthopaedic Institute, funding which made the visit possible.  He and the ORLAU team have been busy collecting and analysing data from lots of volunteer children.  We are looking forward to seeing the results and applying his approach to our patients with hemiplegia.

The Institute have also provided key funding for our postgraduate students.  PhD student Shallum Sardar is looking at the calf muscle, in particular how the morphology of the muscle changes after treatment.  He has been working with Myurah Nathan, our clinical scientist trainee.  Myruah looked at the same children for her MSc project but she was interested in studying the muscle using imaging.  She worked with consultant radiologist Naomi Winn to collect ultrasound elastography data.  Shear Wave Elastography is an imaging technique which aims to quantify tissue stiffness.  Myurah successfully completed her research in the Spring, whilst Shallum continues to collect data.

Another PhD student, Mohammad Alshehab, has been working hard to gain ethical approval for his study, assessing upper limb function in cerebral palsy. Mohammad hopes to quantify the benefits of using Lycra garments.  It is great to see our growing upper limb clinics also reflected in our research.  Along with Raphael and Mohammad’s work we have been successful in gaining funding from the EPSRC for a study entitled ‘Personalised approach to restoration of arm function in people with high-level tetraplegia’, led by Dr Ed Chadwick from Keele University, working with the Trust’s Simon Pickard.


ORLAU Ankle Contracture Correction Device (CCD)

Rehabilitation Engineering

The Rehabilitation Engineering team have seen a number of significant developments this year.  Industrial partners are particularly important for our development work and this year we have developed a new relationship with Rehabilitation Manufacturing Services (RMS) Ltd, who now supply us with the Grillo range of devices, manufactured by Ormesa in Italy.  We have worked hard behind the scenes to develop a relationship that has resulted in them providing  a small ‘stock’ of these devices, which we can use to assess and supply the patient, with RMS charging for them, as we issue them.  This has a dramatic effect on the delivery time for the patient, as they can often take the frame home immediately.  Many of our other devices have much longer lead times for delivery, typically 6-12 weeks, so not only can that cause an inevitable delay, it also results in a further patient appointment.  The Grillo widens our offering for walking device assessments.

Last year we reported the early development of a donning/doffing lever for our ankle contracture correction device (CCD) in collaboration with Ricoh Rapid Fab Ltd.  The original CCD was designed and developed in ORLAU.  We are now supplying the new levers routinely to all ankle CCDs supplied through ORLAU.  In the coming year our intention is to explore opportunities to further improve and commercialise this device with the help of an appropriate industrial partner.

By using money provided by a charitable donation, we are currently developing a safe and simple method of detaching the upper and lower sections of an Adult ORLAU Standing Frame.  This is a much needed development as we see numerous patients with these types of frames who struggle to transport them due to their cumbersome size and weight.  By safely disconnecting the two halves of the device transportation to and from clinic, as well as storage at home should be made much easier for the patients and their families.

Engineer, Simon Marchant is also developing a bespoke bracket to help us attach head supports to our range of standing frames.  The current bracket is a commercial one that we adapt to suit our needs but the time has come to develop our own, that meets the specific needs of our patients.

In conclusion ORLAU is continuing to develop clinical services, alongside teaching and research.  We are always interested in growing our knowledge and have new projects lined up for 2020, including work in the social sciences and a detailed study of the subtalar joint in cerebral palsy.  We will look forward to giving more details about these new projects next year.