Cardiac open reading frame edition to study cardiomyopathies in pigs

ongoing

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.