Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood, with more than 25,000 patients in Europe. It is due to mutations in the DMD gene that preclude the production of the protein dystrophin. In addition to the progressive muscle weakness, 50% of affected individuals have debilitating central nervous system (CNS) co-morbidities, including intellectual disability, neurodevelopmental problems encompassing autism, Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder. These co-morbidities are due to the deficiency of multiple dystrophin isoforms in brain whose expression is differentially affected by the site of the DMD mutation. They represent a major obstacle for patients to live a fully independent life. Current therapies do not address these co-morbidities. The postnatal restoration of one dystrophin isoform using genetic therapies in the DMD mouse model improves the neurobehavioral phenotype. This raises the exciting possibility that some of the CNS co-morbidities could improve with genetic therapies in patients. We need to address several knowledge gaps before considering clinical applications of these therapies: i. dystrophin isoforms localisation in the CNS; ii. which of the neurobehavioural features of the dystrophic mice improve after dystrophin restoration, and circuitries involved; iii. deep phenotype patients to define robust outcome measures. This project developed in partnership with advocacy groups, meets gender criteria and offers for the first time insight into how dystrophins’ affect CNS function, and on the reversibility of the DMD CNS co-morbidities, providing essential information to the field of neurodevelopmental disorders, and for other syndromes arising from dystrophin associated proteins. Our efforts to develop novel therapies that can cross the blood brain barrier could be transformative for the field of neurodegeneration and neurodevelopmental disorders.

The European Rare Diseases Research Alliance (ERDERA) aims to improve the health and well-being of the 30 million people living with a rare disease in Europe, by making Europe a world leader in Rare Disease (RD) research and innovation, to support concrete health benefits to rare disease patients, through better prevention, diagnosis and treatment. This Partnership will deliver a RD ecosystem that builds on the successes of previous programmes by supporting robust patient need-led research, developing new diagnostic methods and pathways, spearheading the digital transformational change connecting the dots between care, patient data and research, while ensuring strong alignment of strategies in RD research across countries and regions. Structuring goal-oriented public-private collaborations targeted at interventions all along the R&D value chain will ensure that the journey from knowledge to patient impact is expedited, thereby optimising EU innovation potential in RD. To support its ambition and missions ERDERA has been designed as a comprehensive and integrated ecosystem of which structure can be compared to an institute encompassing three main parts: (i) funding, (ii) internal (in house) Clinical Research Network that implements research activities targeting clinical trial readiness of RDs and accelerating diagnosis and translation of research discovery into improved patient care, and (iii) related supporting services (Data, Expertise, Education and Training) as well as an acceleration hub that serve external and internal RD community, all supported by all-embracing coordination and strategy and foundational (inter)national alignment.

Muscular dystrophies are severe genetic disorders characterised by muscle wasting, impaired mobility and premature death, which to date remain incurable. Although preclinical and clinical evidence position genetic therapies amongst the key emerging treatments for several genetic conditions, no gene therapy or genome editing strategy has been approved for any muscular dystrophies yet. The lack of robust, human(ised) models enabling precise development of such advanced therapies is a major barrier towards their clinical translation for muscle diseases. To overcome this limitation, we have assembled the multidisciplinary MAGIC consortium to build novel, high-fidelity, models of human skeletal muscle pathophysiology which will be used to develop new vectors for safe and efficacious neuromuscular gene therapy and genome editing. Specific rare (paediatric) diseases targeted by our consortium are Duchenne muscular dystrophy (DMD), X-linked (XLCNM), autosomal dominant (ADCNM) and autosomal recessive (ARCNM) centronuclear myopathies (CNMs), LMNA- and COL6-related congenital muscular dystrophies (CMDs). Microfabrication, microfluidics and human stem cell differentiation technologies will be used to generate disease-specific human myofiber- and muscle-on-chip devices qualified for commercialisation, capable of screening toxicity and cell-specificity of new adeno-associated viral vector (AAV) capsid variants, and unique muscle-specific lentiviruses. Selected vectors will be equipped with novel lineage-specific regulatory elements to further restrict transgene expression to myofibres, muscle stem cells or interstitial fibroblasts, reducing also potential immunogenicity. The same vectors will be loaded with therapeutic genes or with new mutation-independent (for DMD and XLCNM) or mutation-specific (for LMNA- and COL6-CMD) gene editing tools, which will then be validated in dystrophic rodents. Finally, GMP-compatible batches of the top performing vectors will undergo advanced preclinical testing in large animals, preparing them for future clinical translation.