Descripción del proyecto
Un músculo en un chip para desarrollar genoterapias contra las enfermedades neuromusculares
Las distrofias musculares, como la distrofia muscular de Duchenne, son trastornos genéticos graves que causan atrofia muscular, inmovilidad y muerte prematura. A pesar de lo prometedor de las genoterapias y la modificación del genoma, solo se ha aprobado recientemente un producto para una forma de distrofia muscular, debido sobre todo a la falta de modelos fiables de la enfermedad. El equipo del proyecto MAGIC, financiado con fondos europeos, pretende superar esta limitación creando modelos avanzados de músculo humano mediante microfabricación y células madre. Estos dispositivos de músculo en un chip pondrán a prueba nuevos vectores víricos y herramientas de modificación del genoma en busca de estrategias terapéuticas seguras y eficaces. El objetivo de los investigadores es desarrollar vectores perfeccionados que ofrezcan una expresión génica precisa y respuestas inmunitarias limitadas, que puedan validarse en modelos animales de gran tamaño antes de los ensayos clínicos.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
Tema(s)
Convocatoria de propuestas
HORIZON-HLTH-2022-DISEASE-06-two-stage
Consulte otros proyectos de esta convocatoriaRégimen de financiación
HORIZON-RIA - HORIZON Research and Innovation ActionsCoordinador
75654 Paris
Francia