Abstract
(English)
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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 LMNAand
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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