Descrizione del progetto
Terapia genica basata su VEGF per il trattamento delle malattie cardiache croniche
I fattori di crescita endoteliale vascolare (VEGF, Vascular Endothelial Growth Factors) sono proteine di segnalazione prodotte dalle cellule e coinvolte nella creazione di nuovi vasi sanguigni durante lo sviluppo embrionale o successivamente a una lesione, oltre che nella formazione di nuovi collegamenti (circolo collaterale) di vasi sanguigni occlusi. Il progetto HeartGenes, finanziato dall’UE, svilupperà una nuova terapia genica basata su VEGF-B e VEGF-C per il trattamento dell’angina refrattaria e dell’arresto cardiaco, usando il trasferimento di geni esogeni e una nuova tecnologia di attivazione di geni endogeni. I fattori VEGF-B e VEGF-C sono stati selezionati come principali bersagli grazie a prolungati studi sui suini, nei quali hanno dimostrato di apportare i migliori vantaggi fra tutti i VEGF, quali specificità cardiaca, potenti effetti angiogenici e metabolici (VEGF-B) e attività linfangiogenica (VEGF-C).
Obiettivo
BACKGROUND: Therapeutic angiogenesis has great potential for the treatment of severe heart diseases. However, this requires novel approaches and development of new technology.
ADVANCING STATE-OF-THE-ART: We will develop novel VEGF-B and VEGF-C-based gene therapy to treat refractory angina and heart failure (HF). VEGF-B and VEGF-C lead factors were selected from extensive pig studies where they showed the best benefits among all VEGFs, such as relative cardiac specificity, potent angiogenic and metabolic effects (VEGF-B) and lymphangiogenic activity (VEGF-C). Exogenous gene transfer and new endogenous gene activation technology will be developed.
Key new technologies are riboswitch-regulated-AAV8 vectors, Super-Enhancer driven cell-type targeted gene expression, VEGF-B and VEGF-C designer mutants for better efficacy and activation of natural endogenous VEGF-B and VEGF-C expression with promoter binding shRNAs, circRNAs, CRISPR/mutantCas9-VP64-SAM gene activation technology and using a novel concept of the release of promoter pausing. Immunological concerns of AAV8 and usefulness of new synthetic dendrimer carriers will be addressed.
HeartGenes utilizes optimized percutaneous intramyocardial and retrograde venous gene delivery in pig chronic ischemia and HF models, clinically relevant pig exercise test, and 15O-H2O and 18F-FDG PET/MRI imaging to detect treatment effects.
Simultaneously, HeartGenes will take a realistic approach to clinical translation and starts intramyocardial vs retrograde venous riboswitch-AAV8-VEGF-B186 phase I trial in refractory angina as the first step to bring the best novel constructs and the most advanced functional and imaging endpoints developed in HeartGenes to clinical testing at the end of the project.
SIGNIFICANCE: If successful, this approach will bring a paradigm shift to cardiac gene therapy and new therapeutic options for heart diseases. Novel new technologies may also become widely applicable in other areas of medicine.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
70211 KUOPIO
Finlandia