Project description
VEGF-based gene therapy for the treatment of chronic heart conditions
Vascular endothelial growth factors (VEGFs) are signaling proteins produced by cells and involved in the creation of new blood vessels during embryonic development or after injury, and of new bypasses (collateral circulation) to blocked vessels. The EU-funded HeartGenes project will develop novel VEGF-B and VEGF-C-based gene therapy to treat refractory angina and heart failure (HF), using exogenous gene transfer and new endogenous gene activation technology. VEGF-B and VEGF-C factors were selected as lead targets 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).
Objective
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.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
70211 KUOPIO
Finland