Descripción del proyecto
Terapia génica basada en los FCEV para el tratamiento de las afecciones cardíacas crónicas
Los factores de crecimiento endotelial vascular (FCEV) son proteínas de señalización producidas por las células que están implicadas en la creación de nuevos vasos sanguíneos durante el desarrollo embrionario o tras una lesión, así como de nuevos puenteos (derivaciones de la circulación) de los vasos bloqueados. El proyecto financiado con fondos europeos HeartGenes desarrollará nuevas terapias génicas basadas en FCEV-B y FCEV-C para tratar la angina refractaria y la insuficiencia cardíaca (IC) por medio de una nueva tecnología de activación génica endógena y de transferencia génica exógena. Se seleccionaron los factores FCEV-B y FCEV-C como dianas principales a partir de amplios estudios con cerdos, donde mostraron los mayores beneficios de entre todos los FCEV, como la especificidad cardíaca relativa, unos potentes efectos angiogénicos y metabólicos (FCEV-B) y la actividad linfangiogénica (FCEV-C).
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
70211 KUOPIO
Finlandia