Mitochondrial and Neuromuscular Diseases

The WCMR brings together scientists who study the fundamentals of mitochondrial biology with clinicians who focus on mitochondrial disease. This enables us to translate important advances in mitochondrial biology to the treatment of patients with mitochondrial dysfunction.

We are particularly focused on how mitochondrial DNA (mtDNA) mutations occur and spread and the molecular mechanisms that underpin this dysfunction. As the details of how mtDNA is expressed are still incomplete, an aspect of our research concerns increasing the understanding of this complex process. Typically, these studies may involve patient-derived cell lines (primary or iPS-derived culture models), the production of murine or fly models or the deep analysis of patient tissue, provided by our own extensive Newcastle Mitochondrial Research Biobank. Investigations of fundamental mitochondrial biology also include studies in cultured human cell lines and in vitro biochemistry.

Mitochondria perform many crucial functions for the cell, including harnessing oxygen to make the key energy source that powers life. Consequently, defects in mitochondrial function have been found to underpin not only mitochondrial disease but many common disorders including neurological diseases and ageing process itself. Its role in cancer and immune biology are only now beginning to be elucidated. In the Centre we have specific interests in understanding the role of the mitochondrion in the pathogenesis of: 

• mitochondrial disease
• Parkinson's disease
• cancer

The multidisciplinary clinical team within the WCMR provide care and support to >1,000 patients living with mitochondrial disease from within our region and across the UK. Newcastle makes up the largest NHS Highly Specialised Service for Rare Mitochondrial Disorders and works in close collaboration with the other highly specialised services in Oxford and London. This ensures the best standard of care and support across the country for all mitochondrial patients and their families.

Clinical Research

The WCMR team have described newly identified heritable molecular and clinical biomarkers, developed novel diagnostic techniques, progressed our understanding of the natural history of mitochondrial disease and provided new insights into disease mechanisms. These, together with our synergistic links with the NHS Highly Specialised Rare Mitochondrial Disease Clinical and Laboratory teams and our gene discovery programme, have led to improvements in diagnostics and genetic counselling, such that >90% of all patients seen in clinic now receive a confirmed molecular diagnosis.

MitoCohort

WCMR clinical research benefits from a growing longitudinal mitochondrial disease patient cohort (MitoCohort). This cohort, which began in 2008, now includes >1800 patients recruited by the three Highly Specialised Services for Rare Mitochondrial Disorders in the UK (Newcastle (Lead Centre), London and Oxford).  Since 2017, there have been 26 successful applications to access data and the MitoCohort has been a major of source of recruitment to 10 clinical research studies and trials.

Biobank

The WCMR lead the Newcastle Mitochondrial Research Biobank (NMRB). This unique bioresource is an exceptional collection of samples from patients with suspected or diagnosed mitochondrial disease, their family members and healthy controls. To date, there are >3,500 samples that can be accessed by researchers and are crucial to advance research in the field.

The WCMR team are committed to shaping policy both regionally, nationally and internationally for the benefit of the entire mitochondrial community. We continue to build on our experience of engaging policy makers to make a real-world impact and ultimately improve the lives of those affected by mitochondrial disease and dysfunction. This includes policy recommendations that cover the clinical care, disease management, treatment and support of those living with mitochondrial disease.

Mitochondrial Donation

The WCMR team played a key role in engaging policy makers to bring about the required law change in the UK to allow the use of mitochondrial donation, a novel IVF treatment that can reduce the risk of mitochondrial disease being passed from a mother to her child. This landmark policy change involved working closely with many partners but most importantly, patients and families living with mitochondrial disease who engaged politicians with their personal experiences of the condition. This was hugely successful and saw the Mitochondrial Donation Regulations approved into UK law on 4th March 2015.

The team continue to shape policy through the generation of new clinical guidelines that have been adopted nationally and internationally.  We have also established new services, including the world’s first licensed clinical pathway for mitochondrial donation.

In the WCMR, we have always put our patients and their families at the centre of everything we do and strive to ensure our research remains patient focussed and driven by invaluable patient input. We are fortunate to have a highly motivated and enthusiastic patient community who continue to play a key role in developing our research strategy at every stage of the process, from initial grant proposals to experimental co-design, developing patient outcome measures, engagement activities and dissemination.

This highly successful approach to our patient involvement is key to the ongoing success of our Centre and regular focus groups ensure we have an empowered patient community with opportunities to share their valuable insight and experiences of living with mitochondrial disease for the benefit of all.

Events

We host annual engagement days in Newcastle with our charity partner The Lily Foundation for mitochondrial patients and their families, with many travelling from across the UK to hear about research updates in mitochondrial disease and meet other people living with the condition. A highly successful aspect of our engagement day is a ‘Meet the Researcher’ session in which our WCMR scientists have an opportunity to engage patients and families with their research through fun and interactive activities. Evaluation of the event has revealed that both the researchers and patients find this enjoyable and incredibly beneficial.

Our Centre’s working environment fosters internal interdisciplinary collaborations, such as joint supervision of PhD students and postdoctoral scientists, and provides a broad programme of training in clinical and fundamental science that will continue to be strengthened and diversified. This includes:

1. early career researchers, fellows and new WCMR principal investigators (PIs) who join the WCMR are given bespoke training as part of the Newcastle University PI Development Programme to improve their leadership and management skills.
2. clinical researchers within the WCMR have taken advantage of similar NUTH staff training programmes
3. postgraduate students through to Fellows within the WCMR are offered Academic Mentorship to assist with career and personal development.
4. a new initiative within the WCMR is a bespoke PhD student training programme to help the next generation of researchers (for more information: https://www.newcastle-mitochondria.com/wp-content/cache/all/career-path-beyond-phd-workshop/index.html). We also provide specific training and support for technical staff.
5. engagement training.

All training and development needs, both professional and personal, are continually evaluated for all staff (academic and support) with courses available through the University and formally considered at annual Performance and Development Reviews supported by the Faculty.

As well as training and education for all members of the WCMR team, we recognise the importance of extending this beyond our Centre to increase understanding and raise awareness of mitochondrial disease and dysfunction with a diverse audience. We currently run a highly successful MRes module in Mitochondrial Biology at Newcastle University and are committed to educating healthcare professionals in the diagnosis, clinical management and care of patients with mitochondrial disease.

The JWMDRC team has substantial basic research experience in NMD diseases. We have a long-standing interest in unravelling the molecular pathways governing the process of muscle degeneration in different models of NMD disease including:

• muscular dystrophies
• congenital myopathies
• spinal muscle atrophy
• metabolic myopathies 

We aim to identify new targets for treatments that could stop or slow down the progression of these diseases. We have considerable experience in cell culture work and high-throughput screening of drugs aimed to revert the ongoing degenerative process. We have active collaborations with several pharmaceutical companies testing new compounds in our cellular and animal models.

Our basic research is focused on the identification of disease-causative genes, biomarkers and modifiers of the natural history of neuromuscular diseases. We are interested in unravelling the mechanisms leading to muscle degeneration and orchestrating muscle regeneration in patients with muscular dystrophies and other genetic myopathies. We use both preclinical murine models, and human tissue.

Our research outputs contribute towards the development of treatments for different patient populations. This includes studying and optimising therapeutic compounds to deliver better, safer and more effective treatments. In this regard we are currently involved in the discovery and pre-clinical development of antifibrotic, antiadipogenic and pro-regenerative drugs for the muscles. As well as the development of nanoparticles to carry therapeutic compounds to the muscle. 

Ultra-rare NMD diseases

We have a special interest in gene identification for ultra-rare NMD diseases and in extending our knowledge of novel variants in known disease genes. One of our interests are the proteins associated with the dystrophin-glycoprotein complex and we are working on the role of dystrophin function in the brain.

We are involved in deciphering the molecular pathways activated by the accumulation of glycogen in Pompe disease. We have identified several new disease genes through our international next generation sequencing projects, such as MYO-SEQ and Solve-RD. We are investigating potentially disease-causing variants in non-coding regions, genetic modifiers and concepts of digenic and oligogenic inheritance.    

Another research interest of our team is muscle fibrosis and adipogenesis. We are investigating a newly identified type of stem cells called fibro-adipogenic precursor cells. We have developed a protocol that enables us to isolate these cells from patients’ muscle biopsies and to study their role in disease pathogenesis. We have established close collaborations with colleagues at the Hospital Sant Pau in Barcelona, the Institute of Myology in Paris and Children’s Nationwide Hospital in Washington to study these and other stem cells obtained from muscle biopsies of patients.

Biobank

The JWMDRC manages the Newcastle Biobank for Rare and Neuromuscular Diseases. During the past 10 years, the biobank has assembled a collection of more than 15,000 anonymised samples. This has resulted in a number of high-profile research publications, supporting translational research. Our research has obtained significant funding from research councils (MRC and ERC), Wellcome Trust, European Commission, patient organisations and public-private partnerships. 

The JWMDRC runs multidisciplinary paediatric and adult clinics for over 2500 NHS patients per year with a range of neuromuscular diseases throughout the North of England. We lead the nationally commissioned service for limb girdle muscular dystrophy and overlapping diseases. Over 10,000 patients have accessed this service from across the world in the past two decades.

We also provide the opportunity for visiting academics and doctors to gain experience working within the team, providing unique access to clinic and various clinical activities. Recently we have implemented innovative therapies developed through clinical trials in patient care via commissioned licenced products, and expect to be able to deliver the first gene therapy for SMA in clinical setting in the near future. 

Research

We are a leading site for international research studies and clinical trials, supported by a high quality team of clinicians, clinical evaluators and clinical trial coordinators.

Our expertise and facilities have led to our involvement in more than 40 clinical trials and natural history studies over the past 8 years. We have established outcome measures for clinical research in various neuromuscular diseases.

We are currently leading the first DMD gene therapy trial, and the first gene therapy study in adult patients with Pompe disease.

We are breaking new ground by fostering collaborations in new countries and regions. Exploring how practices tried and tested in the NMD field can benefit other populations, in line with the University’s vision of ‘From Newcastle. For the World’.

Rare disease and NMD patients in many regions of the world are yet to benefit from diagnosis, face stigma and minimal access to care. In the spirit of the UN Sustainable Development Goals, the JWMDRC is committed to ensuring that no patients are left behind and are keen to advocate and develop activities targeted to address this accordingly.

MRC International Centre

We are a member of the MRC International Centre for Genomic Medicine in Neuromuscular Disease, collaborating with centres in Brazil, Turkey, India, South Africa and Zambia to develop cohorts of genetically diagnosed NMD patients. Furthermore, we are building on existing Newcastle University partnerships with Sudan, Tanzania and Egypt and the African collaborating centres in the ICGNMD to increase awareness and recognition throughout Africa in the INCLUDE-NMD Consortium. 

There is much to be learnt about presenting phenotypes for NMDs in different ethnic populations. The JWMDRC is therefore building on existing partnerships where measurement of disease progression is well understood. The International Clinical Outcome Study for Dysferlinopathy, led by our team, has expanded to include partners from Santiago de Chile and through an MRC/ KHIDI partnership grant is now working to include Pusan National University in South Korea. 

TACT

We are also utilising our research experience and expertise in NMDs to establish innovative models and resources in other disease communities. The TREAT-NMD Advisory Committee for Therapeutics (TACT) was developed and coordinated by a secretariat based at the JWMDRC, initially funded by the European Union (FP6). TACT is a unique multi-disciplinary international group of drug development experts. It meets twice a year to review and give objective advice on the development pathway of therapeutic programs in NMDs.

Since its establishment in 2009, TACT has become a self-sustaining resource and has reviewed over 60 applications for advice from both academia and industry, in thirteen different NMDs. To build opportunities for other rare disease communities to benefit from the lessons learned in the NMD field, we have produced an Advisory Committee for Therapeutics (ACT) toolkit. Developed through our engagement in the European Joint Programme for Rare Diseases (EJP RD), it will support other rare disease networks, particularly the ERNs - to replicate the TACT model.

Since 2012, the JWMDRC has supported and led numerous projects dedicated to any and all diseases classed as rare. This reflects the status of rare diseases as a priority area for action at national and European levels. Through leadership of European Joint Actions, experts in the Centre engaged with the European Expert Groups for Rare Diseases to elaborate numerous sets of policy recommendations. These addressed topics ranging from Cross-Border Genetic Testing to the Incorporation of Rare Diseases into Social Services and Policies.

A particular emphasis was placed on working with national authorities –typically Ministries of Health – to support the creation and adoption of National Plans and Strategies for rare diseases. This work contributed strongly to the adoption of plans/strategies by 25 of 28 EU MS by 2020. 

European Reference Network

A particular success of this policy activity was our role in the European Reference Network (ERN). The JWMDRC team supported the conceptualisation and implementation of ERNs. Under the RD-ACTION project (2015-18), organised 8 major workshops to enable the 24 ERNs to address their diverse and shared responsibilities. Enabling agreement of good practices and promoting the progress of these landmark pan-European entities for rare disease care and research. 

Our policy activities have been focused most recently on the creation of a new set of policy recommendations designed to guide the field towards a brighter 2030.  These recommendations are intended to stimulate a new policy framework for Europe (with which countries within and beyond the EU should engage).

It is important to make sure that we educate and communicate our research and care advances to the patient communities we serve. The Centre’s clinical and networking teams (together with TREAT-NMD have:

• coordinated the publication of patient information in multiple languages about standards of care
• produced project updates for advocacy newsletters
• developed digital tools such as an App for children about clinical trials

Working with patients as participants and educating the community about the latest developments is an important part of our translational research efforts. We ensure significant representation of the patient community in our advisory boards for basic research and other projects. For example, launched in 2020 and actively supported by our team, DMD Care UK works directly with both the patient and clinical community to agree and improve standards of care. A patient and family focus group is part of decision making across the project, where the patients’ voice is as loud as the clinicians’.

Events

We have organised education and information days for patients and families at our site in Newcastle. Encouraging engagement and empowerment and bringing people together with support from patient organisations and other funders to hear about research and care in their own condition. These have included events for patients with limb girdle muscular dystrophy and Duchenne muscular dystrophy. As well as caregiver information days with MDUK and Duchenne UK.

Online webinars have been important throughout the pandemic, and we plan to move back to the valuable face-to-face events as soon as this is possible. Many of our projects and initiatives have enhanced our understanding of how to form equitable and meaningful partnerships with patients in all activities relevant to rare diseases. Ranging from shaping care services to policymaking, supporting advocacy to co-designing and delivering research. Our team recently authored a set of high-level recommendations aimed at policymakers and national authorities, on how to build stronger patient partnerships.

Breakthroughs in diagnostics and treatments or best ways to manage and deliver care for NMD patients only has impact when it has influence on practice. Education and training to make sure that expertise and knowledge is where it needs to be is a key activity for our team. We have been instrumental in the organisation and delivery of international expert masterclasses for clinicians as part of our role in the TREAT-NMD network. We have also facilitated local and national workshops and events for families affected by NMD conditions as well as for the medical practitioners that care for them.

Experts in our networking team have coordinated international training opportunities in a number of genetic NMD diseases. This ensures the latest standards of care or understanding of new therapies reaches a wide international audience of practitioners. We have worked with groups of pharmaceutical companies to offer general awareness training for diagnostics and care as well as specific training linked to new therapies or treatments. Companies include:

• PTC
• Roche
• Biogen
• Sarepta

Through our involvement in the TREAT-NMD network, the JWMDRC coordinated a programme of seven DMD and SMA masterclasses over five years across Europe. Up to 60 clinical experts attended each one, from Amsterdam to Lisbon to Warsaw. They benefitted from lectures, interactive sessions and small break out groups for discussion about best practice and problem solving with a panel of key opinion leaders. 

The DMD Hub, is coordinated in partnership between our team and DMD-UK. It’s aim is to increase clinical trial capacity for patients with Duchenne muscular dystrophy. It has developed a training and education programme for nurses and clinical trial coordinators and is responsive to the needs identified by the staff within the networks. Currently there is a focus on providing information and training on gene therapy clinical trials and delivery of a licenced gene therapy.

conect4children

Based on our experience of developing both online and face-to-face courses, as well as our experience in rare diseases in general, we were invited to lead on the development of short online courses within conect4children (c4c). This is a pan-European paediatric clinical trial network funded by IMI2 that aims to provide better medicines for children of all ages, by facilitating quality clinical trials. By creating a number of cross-cutting short courses for clinical trials staff, we harness and disseminate the experience and knowledge of partners from a number of well-established disease specific networks for the benefit of the c4c network and paediatrics as a whole. As part of the c4c education programme, we will be developing a course which will allow other centres to benefit from our knowledge and support them to prepare for gene therapy clinical trials.

We have a long tradition of working to establish networks and collaborations with stakeholders from across the neuromuscular landscape. Our experienced networking team provide project management, administrative and subject matter expertise across a portfolio of national and international projects. We have had great success in securing funding for such projects over the years and have received in excess of £10m in grant income over the last 10 years. This places us firmly at the centre of the neuromuscular and rare disease community.

We have active patient and public involvement programmes. These include interactions and close working relationships with NHS services as well as many different patient organisations. As leading specialists in the neuromuscular field we have a proven track record of success in collaboration with commercial organisations around the world. Our established partnerships with biotech and pharmaceutical companies help develop new therapeutics and accelerate clinical studies. We are experienced in the set-up and coordination of national and international neuromuscular patient registries and run 7 disease specific registries from the centre, collecting data on over 4,000 neuromuscular patients.