Gene therapy CM-YAP^on protects the mouse heart from myocardial infarction

Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function¹. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair^2,3. Here we develop an adeno-associated virus 9-based therapy, termed CM-YAP^on, which enables transient expression of an active YAP variant (YAP5SA) in CMs after exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle reentry and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers cardioprotection and reduces cell death across multiple cardiac cell types. These findings reveal the therapeutic potential of reversible gene activation for ischemic heart disease.