Description du projet
Thérapie génique pour les maladies cardiaques
La cardiomyopathie dilatée est une maladie progressive associée à l’élargissement des chambres du cœur. Cela signifie que le cœur ne se contracte pas normalement et ne parvient pas à pomper le sang efficacement, entraînant souvent une insuffisance cardiaque. Le projet Cor-Edit-P, financé par l’UE, travaille sur une approche de thérapie génique pour corriger les mutations des gènes des cardiomyocytes associées à la cardiomyopathie dilatée. Les chercheurs testeront une stratégie curative de modification génétique à l’aide de vecteurs viraux adéno‑associés dans des modèles porcins de la maladie. L’objectif ultime est de traduire les résultats dans des protocoles cliniques capables d’améliorer la fonction cardiaque, de réduire le risque d’arythmie et d’accroître la qualité de vie des personnes touchées.
Objectif
Heart failure represents a common cause of death in European societies and is frequently based on dilated cardiomyopathy (DCM) which might be caused by mutations in cardiomyocyte genes. While no specific treatment exists, new therapeutic options are a major unmet clinical need.
As attractive novel key approach, Cor-Edit-P will use Crispr-Cas9 based gene editing for distinct gene therapy of genetic cardiomyopathy, using pigs as a unique, clinic-related large animal model system. My lab tailored highly cardiotropic adeno-associated viral (AAV) vectors and their use in pigs in vivo, applying precise, reliable and versatile Cas9 technology. Pioneering this approach, we were able to restore significant dystrophin expression in muscles and hearts of pigs suffering from Duchenne muscle dystrophy.
Exploiting unique and cutting-edge technology, Cor-edit-P aims at specifically eliminating the underlying cause of genetic DCM to improve cardiac function, reduce the risk of deadly arrhythmias and increase span and quality of life.
Cor-edit-P will
- generate currently lacking porcine models of genetic cardiomyopathy, using AAV-Cas9 to induce mutations in sarcomere genes, e.g. titin (TTN) and ß-myosin heavy chain (MYH7);
- exercise curative Crispr-Cas9 mediated gene editing of DCM in pigs in vivo, using the PLN-R14del mutation in the phospholamban (PLN) gene as prominent example;
- use human patient-derived PLN-R14del ventricular progenitor cells for gene correction ex vivo followed by transplantation of corrected cells into PLN-R14del pigs.
Our approach implements a new paradigm for treating genetic cardiomyopathy and develops Crispr-Cas9 based gene therapy in pigs to foster clinical translation. Our work will influence the development of gene therapy by industry and academia and will benefit patients suffering genetic cardiomyopathy, but also further genetic diseases which are manifold prevalent in Europe.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-ADG - Advanced GrantInstitution d’accueil
81675 Muenchen
Allemagne