Description du projet
Une thérapie d’édition des gènes pour traiter les cardiomyopathies
Les cardiomyopathies héréditaires sont une cause majeure de mort cardiaque subite et sont dues à des mutations dans les gènes codant des protéines sarcomériques du muscle cardiaque. Comme il n’existe aucun traitement curatif des cardiomyopathies, le projet Edit-hCOs, financé par l’UE, voudrait utiliser la technologie de pointe d’édition du génome CRISPR-Cas9 pour corriger les mutations responsables de ces maladies. Les chercheurs ont développé des organoïdes cardiaques humains présentant des mutations causant des cardiomyopathies afin de tester l’efficacité des modifications génétiques et de corriger les effets de la maladie. Le projet permettra également de générer des modèles de souris humanisées portant les mêmes mutations que les patients afin d’étudier la sécurité et l’efficacité des traitements génétiques pour le traitement permanent des cardiomyopathies.
Objectif
Inherited cardiomyopathies are a major cause of sudden cardiac death and are caused by mutations in genes encoding sarcomeric proteins. With an incidence of 3 per 1,000 adults within the European population, inherited cardiomyopathies present a substantial burden to the healthcare services of all European nations. Although a few medications can slow the progression of the disease, today there is no cure for cardiomyopathies. The CRISPR-Cas9 precision genome editing technologies, base and prime editing, can permanently edit point mutations of genes, making them ideal tools to treat cardiomyopathies. To demonstrate the efficacies and therapeutic benefits of these editors in correcting cardiomyopathy-causing mutations, it is necessary to develop robust in vitro models of mature human cardiomyocytes that recapitulate the cellular complexity of the human heart. In the Edit-hCOs project, I will generate and characterize human cardiac organoids (hCOs) harboring clinically relevant cardiomyopathy-causing mutations in the FLNC gene, which encodes for the sarcomeric protein filamin C. hCOs will be generated as three-dimensional scaffold-free cardiac microtissues using tri-cellular combinations of human induced pluripotent stem cell -derived cardiomyocytes, cardiac fibroblasts, and cardiac endothelial cells. Then, I will deploy base and prime editors to fix common FLNC gene mutations in the hCOs, and I will characterize their molecular and functional improvements following correction. In addition, I will generate humanized mouse models harboring the same mutations as patients for future studies on delivery, therapeutic safety, and efficacy of the genome editing components in vivo. Completion of the Edit-hCOs project will allow me to establish a completely innovative and ambitious research line focused on the permanent treatment of cardiomyopathies. This will establish a crucial and important pre-clinical step towards therapeutic genome editing of cardiovascular diseases.
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
35122 Padova
Italie