THE WOLFSON CENTRE FOR INHERITED NEUROMUSCULAR DISEASE (CIND).

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, Mrs Kate Strachan

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)

The CIND Muscle Team is recognised as a ‘Centre of Clinical Excellence’ for paediatric and adult patients by the Muscular Dystophy UK (MDUK) Charity, reviewed every three years, and was on the 2019 short-list for “Best Team” at RJAH. During COVID 19 they have continued their clinical work and data collection for the national databases for both DMD (Duchenne Muscular Dystrophy) and Spinal Muscular Atrophy patients, with many assessments taking part virtually. A study assessing the usefulness/accuracy of the DMD NSAA (North Star Ambulatory Assessment) was performed via video and assessed independently by two physiotherapists. An abstract has been submitted to the British Paediatric Neurology Association Meeting in Belfast in January 2021. During COVID 19, they have also continued  clinical trials and home dosing with virtual and remote visit monitoring and, more recently, face to face visits within guidelines. The team and research nurses are committed to ensuring these studies continue and the patients receive their medication.

The Muscle Team has participated in multicentre studies of the natural history of SMA (SMA Reach project and iSMAc study) and the the Sarepta natural history study of Duchenne Muscular Dystrophy. The pharmaceutical trial, SIDEROS, a placebo-controlled trial with idebenone, targeting mitochondrial function in Duchenne muscular dystrophy, is now in extension phase and one patient has fully completed. The Italfarmaco study is about to enter the extension phase and both are fully recruited.

Legend = ” Participants at the “Sewry-Fest”: Caroline, and husband Steve, are 3rd and 4th from the right.”

Within the Laboratory Research Team, Darija Šoltić passed her PhD with minor corrections, having successfully defend her thesis entitled “Proteomics-based identification and characterisation of spinal muscular atrophy disease pathways” by video call in June 2020. Following publication of work from her thesis in the Human Molecular Genetics journal in 2019, Darija published an invited commentary article in the Neuroscience Insights journal, together with her supervisor, Dr Heidi Fuller. In early 2020, Darija joined the Ruepp group at the UK Dementia Research Institute, King’s College London as a postdoctoral researcher, where she continues her research on neuromuscular disease, but now with a focus on amyotrophic lateral sclerosis.

Spinal muscular atrophy

Prof Tracey Willis and Dr Richa Kulshrestha have been part of the team that secured MRC funding of £968,000 over 3 years for “Segmental Assessment of Trunk Control (SATCo) in SMA” in a collaboration with Manchester Metropolitan University. The Clinical Team has also extended its collaboration with the University Hospital of North Midlands with both adult and paediatric type 2 and type 3 SMA patients (less severe than type 1 SMA) receiving  the drug Nusinersen as part of a  Managed Access Agreement after approval of this new “wonder drug” by NICE and NHS England (adults to begin in October 2020). Nusinersen is an antisense oligonucleotide drug that targets the SMN2 gene, causing it to make more complete SMN protein to compensate for the missing SMN1 gene in SMA.

Postdoctoral researcher, Dr Sharon Owen, is now in the second year of a laboratory-based project investigating molecular mechanisms involved in different types of spinal muscular atrophy (SMA). This work is funded by Sparks and Great Ormond Street Hospital and is led by Senior Lecturer, Dr Heidi Fuller.

Prior to ‘COVID-19 lock-down’, Dr Fuller and Dr Owen attended the SMA Europe meeting in Evry, Paris (5-7^th February 2020) and gave podium presentations on two aspects of their work. Dr Fuller talked about protein changes observed in the hearts of two mouse models of SMA, in particular, the increased presence of a protein called Lamin A/C which may alter the stiffness of the nucleus in these heart cells and hence impact on the ability of the heart to function optimally. Dr Owen’s presentation was based on work investigating protein expression in cells obtained from the skin of SMA patients with varying severity of SMA. It is hoped that this information will provide a means of tracking disease severity, for example, to establish the efficacy of current treatment regimens.

Dr Owen presented an update on the work being carried out on the SMA mouse models at the virtual UK SMA 2020 meeting (10-11^th September 2020) suggesting that other key proteins involved in the mechano-sensing machinery of heart cells may be involved in SMA-related cardiac dysfunction. Prof Willis was a member of the Expert Clinical Panel at the same SMA Research meeting.

Facioscapulohumeral Dystrophy (FSHD).

The Clinical Team has successfully completed a pilot study of arm cycling in patients with facioscapulohumeral dystrophy. The results were presented at the UK Neuromuscular Translational Research conference in Newcastle-upon-Tyne and funding has been secured for a PhD studentship to look at this in more detail with collaboration with Keele University. Funding was also secured for another study in this patient group to study biomarkers and their variation with exercise, but is on hold because of COVID 19.

Congenital muscular dystrophy

Congenital muscular dystrophy (CMD) refers to a rare group of muscular dystrophies that become apparent at or near birth. There is no cure, and affected individuals experience progressive muscle weakness and often develop heart disease that can result in sudden death. Although many of the causative mutations are now clear, the ability to identify suitable therapeutic targets is hampered by a lack of understanding of the molecular pathways acting downstream from the defective gene(s) to modulate disease progression. Emily Storey, PhD student within CIND, published a review article in the Neuromuscular Disorders journal, in which she highlighted gaps in knowledge in relation to CMD and areas for future work. Her own research project, which is now in to its second year, involves examining and characterising molecular pathways involved in CMD using a range of laboratory techniques, including proteomics technology. This work will help us to understand why certain genetic mutations lead to congenital muscular dystrophy and will identify potential therapeutic strategies for testing in vivo.

Legend = ” Emery-Dreifuss muscular dystrophy: the two forms of nesprin are found at different locations in the heart.”

Popeye Proteins and Cardiac Conduction.

Dr Ian Holt has continued to characterize monoclonal antibodies (mAbs) against Popeye (POPDC) proteins by mapping exactly where the mAbs bind to the protein antigen sequence in collaboration with Prof. George Baillie’s group at Glasgow University.

Mutations in Popeye proteins can cause a form of limb-girdle muscular dystrophy with conduction defects, similar to Emery-Dreifuss muscular dystrophy. In a collaborative project with Thomas Brand of the National Heart and Lung Institute (London), funded by the British Heart Foundation, Dr Ian Holt has shown an interaction of both POPDC1 and POPDC2 with both cardiac actin, annexin A5 and XIRP1 (Xin actin-binding repeat protein 1) at important locations for cardiac conduction (intercalated discs and transverse tubules). Both XIRP1 and POPDC1/2 are proteins known to be associated with heart pathology and cardiac conduction defects. This work has been submitted for publication.

The MDA Monoclonal Antibody Resource.

Monoclonal antibodies produced by CIND and the cell lines that produce them have been given a safe and permanent home in the Developmental Studies Hybridoma Bank (University of Iowa). These mAbs have played a major role worldwide in clinical trials of new treatments for the muscular dystrophies. Dr Le Thanh Lam is continuing to respond to antibody requests from academic researchers worldwide and, in August 2020, we began to support the cost of this service by making a small charge to recipients. Prof. Morris initiated a new collaboration with the University of California at Irvine in 2020 aimed at developing novel antibody-based treatments to depress inflammation in Duchenne Muscular Dystrophy.

Nemaline Myopathy

Nemaline myopathies are named after a structural body seen in muscle biopsies. Defects in several genes are known to cause various clinical forms of nemaline myopathy. One of the most common genes affected codes for a protein called nebulin, one of the largest proteins known in the human body. The team at RJAH have developed antibodies that specifically recognise two different forms of nebulin. These are expressed at different times during muscle development and may have a role in particular types of muscle fibres . Research by the group is examining whether different forms of nebulin might relate to the differential involvement of certain muscles in particular diseases of muscle, including nemaline myopathies. Mutations in some of the protein partners of nebulin also cause nemaline myopathy and we are testing the possibility that the partnership is with only one of the two nebulin forms.