Limb Girdle Muscular Dystrophies (LGMDs) are a group of rare, slowly progressive conditions that lead to muscle weakness and loss of mobility. The second most common subtype LGMDR2, also known as Dysferlinopathy, affects around eight people per million.

Despite Dysferlinopathy’s impact on patients and families, there was limited understanding of how the disease progresses, little investment in clinical trials and no functional outcome measure to make a clinical trial feasible within a reasonable period of time.

To address these challenges, the John Walton Muscular Dystrophy Research Centre (JWMDRC), working with international partners and supported by the Jain Foundation, established the International Clinical Outcome Study (COS) for Dysferlinopathy. Running for more than 14 years across 21 sites in eleven countries and involving more than 300 participants, the study was designed to improve understanding of the condition, develop a disease specific clinical outcome measure, encourage investment in treatment development, inform and improve care.

Developing tools and evidence to support future trials

One of the study's most significant achievements was the development of the first validated functional outcome measure for LGMD, the North Star Assessment for Limb Girdle Muscular Dystrophies (NSAD). Having first been designed for use in dysferlinopathy, this measure is now being used more broadly as a primary outcome measure in 11 interventional clinical trials and has been adopted in 24 natural history studies, studies that track how a disease or condition progresses over time, across LGMDs, and a growing number of other rare muscular dystrophies.

The study has also increased understanding of disease trajectory and delivered the largest muscle imaging (MRI) study undertaken in LGMD. Data and expertise generated through the programme have supported protocol development advice for four academic consortia, while the international consortium has created a network of 21 trial sites that can support future research and recruitment.

Alongside these achievements, the study has generated 18 peer-reviewed publications and enabled approved data and sample access requests from both academic and industry partners, helping to maximise the use of the data for future research.

Supporting patients, researchers and standards of care

The programme has contributed to improving care as well as research. Findings from the study are informing the development of Standards of Care Guidelines for Dysferlinopathy, while outcome measures developed through the programme are already being used in clinical settings in Newcastle and elsewhere to inform care management.

Support from the NIHR Clinical Research Facility: Newcastle enabled delivery of the study locally, while NIHR Biomedical Research Centre: Newcastle support helped provide study leadership and support funding applications. Due to investment in the JWMDRC biobank the collection of samples through this international study has created a well-curated resource to support future research.

These samples have already contributed to the development of a new diagnostic test and have supported further biomarker research and machine learning studies. The programme has also strengthened international collaborations, including developing partnerships with centres in India, Chile, South Africa and South Korea, and supported training opportunities, PhD studentships and workforce development in rare disease research.

Building on the foundations for future research and care

The study continues to generate new opportunities for research. Current work includes analysing longer-term natural history data to better understand prognostic features of disease progression and investigating potential biomarkers using samples collected through the study.

Additional funding has been secured to support biomarker research, extend the study and introduce wearable technologies, linking with the NIHR Biomedical Research Centre: Newcastle Digital Health, Ageing Innovation and Inclusion Theme. Researchers are also seeking funding to investigate genetic modifiers and to increase the diversity of study populations through initiatives such as building on the strong partnerships with centres in India.

The most exciting new opportunity for research is the sister study, COS PrePARED, the Clinical Outcome Study in PRe- and Early-symptomatic PAtients with REcessive Dysferlinopathy, also developed in close collaboration with funding partner the Jain Foundation.

Increasingly early stage diagnoses of muscular dystrophies are being generated through coincidental blood tests, such as abnormal liver results or CK before motor function symptoms develop. This novel, single centre study offers the opportunity to gain valuable insights into the earliest stages of symptom onset in order to increase recognition of this rare disease, quantify the earliest physical signs of disease progression, establish the impact of potential risk factors, bolster the clinical care support provided to early diagnosed patients and their local care teams,and determine the right time to dose with any future approved therapeutic targets. This model is applicable to other rare neuromuscular diseases. Future plans include supporting implementation of standards of care, expanding the use of the NSAD, developing a clinician-entered patient registry to support clinical trial recruitment, and extending natural history studies to other rare neuromuscular disorders through the LifeArc Centre for Acceleration of Rare Disease Trials, coordinated by Newcastle. The programme is also continuing to work closely with pharmaceutical industry partners to support future clinical trial planning.