Descrizione del progetto
Muscolo su chip per sviluppare terapie geniche per le malattie neuromuscolari
Le distrofie muscolari, come la distrofia muscolare di Duchenne, sono gravi malattie genetiche che causano deperimento muscolare, immobilità e morte precoce. Nonostante la promessa delle terapie geniche e dell’editing del genoma, solo un prodotto è stato recentemente approvato per una forma di distrofia muscolare, soprattutto a causa della mancanza di modelli di malattia affidabili. Il progetto MAGIC, finanziato dall’UE, intende superare questa limitazione creando modelli muscolari umani avanzati utilizzando la micro-fabbricazione e le cellule staminali. Questi dispositivi muscolo su chip testeranno nuovi vettori virali e strumenti di editing genico per strategie terapeutiche sicure ed efficaci. I ricercatori intendono sviluppare vettori raffinati che offrano un’espressione genica precisa e risposte immunitarie limitate, che possano essere ulteriormente convalidati in modelli animali di grandi dimensioni prima della sperimentazione clinica.
Obiettivo
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.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicinephysiologypathophysiology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicineneurologymuscular dystrophiesduchenne muscular dystrophy
- natural sciencesbiological sciencesgeneticsgenomes
Programma(i)
Argomento(i)
Invito a presentare proposte
HORIZON-HLTH-2022-DISEASE-06-two-stage
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HORIZON-RIA - HORIZON Research and Innovation ActionsCoordinatore
75654 Paris
Francia