Descrizione del progetto
Una terapia basata sull’editing genico per trattare le cardiomiopatie
Le cardiopatie ereditarie, che sono una delle principali cause di morte cardiaca improvvisa, vengono provocate da mutazioni nei geni che codificano le proteine sarcomeriche nel muscolo cardiaco. Non esiste alcuna cura per le cardiomiopatie, motivo che ha spinto il progetto Edit-hCOs, finanziato dall’UE, a utilizzare la tecnologia di precisione basata sul sistema CRISPR-Cas9 per l’editing del genoma allo scopo di correggere le mutazioni responsabili di tali patologie. I ricercatori hanno sviluppato organoidi cardiaci umani caratterizzati da mutazioni che provocano le cardiomiopatie al fine di verificare l’efficacia degli editor genici e di mitigare gli effetti di queste malattie. Il progetto genererà inoltre modelli murini umanizzati contraddistinti dalle stesse mutazioni dei pazienti allo scopo di studiare la sicurezza e l’efficacia dei trattamenti genici per un trattamento permanente delle cardiomiopatie.
Obiettivo
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.
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
35122 Padova
Italia