Grant Award Details
- To determine if simultaneous delivery of modified RNA (modRNA) encoding 4 cyclin associated genes (CDK1, CDK4, CCNB1 and CCND1, collectively 4F) delivered in lipid nanoparticles (LNP) via intramyocardial injection promotes regeneration of the heart in congestive heart failure. (Therapeutic candidate: 4F modRNA LNP)
Grant Application Details
- Modified RNA-Based Gene Therapy for Cardiac Regeneration Through Cardiomyocyte Proliferation
Efficacious and safe intramyocardial delivery of modified mRNA encoding cell cycle regulators as a gene therapy for cardiac regeneration through resident cardiomyocyte proliferation.
This project would provide disease-modifying gene therapy for people with heart failure due to loss of cardiac muscle, a leading cause of deaths in the US, using novel modified mRNA delivery.
Major Proposed Activities
- Human iPS-derived cardiomyocytes successfully transduced with modified RNA (modRNA) encoding human cell cycle regulators.
- Successful delivery of modRNA encoding cell cycle regulators into mouse hearts
- Successful stimulation of human cardiomyocyte division in a dish and adult mouse cardiomyocytes in vivo with modRNA delivery of cell cycle regulators
- Efficacy of modRNA delivery of cell cycle regulators on improving ejection fraction in mice with acute myocardial infarction (MI).
- Efficacy of modRNA delivery of cell cycle regulators on improving cardiac function in chronic post-MI rats.
- Evaluate safety parameters for modRNA delivery of cell cycle regulators in mice and rats.
Heart disease is a leading cause of mortality and end-stage heart failure carries a 50% two-year mortality. Few treatments are available and even those do not alter the basis for disease, resulting in ultimate need for heart transplant. We propose gene delivery mediated by modified mRNA, as used in COVID vaccines, to reprogram adult cardiomyocytes transiently into a proliferative state for cardiac regeneration, thereby improving heart function.