Muscular dystrophies leave children with failing muscles and shortened lives, and no gene therapy has yet been approved for any of them. The core problem is that researchers lack realistic human muscle models to test these therapies before moving to patients. The MAGIC consortium is building "muscle-on-chip" devices—tiny platforms lined with living human muscle cells grown from stem cells, complete with microfluidic channels that mimic blood flow. These chips will screen new viral vectors for safety and cell specificity, and the best candidates will carry therapeutic genes or gene-editing tools tailored to four rare paediatric muscle disorders, including Duchenne muscular dystrophy. If successful, the project will deliver validated, GMP-compatible vector batches ready for clinical trials in humans. This matters because current animal models often fail to predict how therapies behave in human muscle tissue, stalling progress for decades. The chips themselves could become commercial products, accelerating drug development for other muscle diseases beyond the four targeted here.
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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 centronuclear myopathy (XLCNM), LMNA- and COL6-related congenital muscular dystrophies (CMDs). Microfabrication, microfluidics and human stem cell differentiation technologies will be used to generate disease-specific 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 mutationindependent (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.
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