Novel gene therapy CM-YAPon protects the mouse heart from myocardial infarction - MI

Myocardial infarction (MI), which affects about 3 million people globally each year, permanently damages the heart and reduces cardiac function1. Recent studies have indicated that activating YAP in cardiomyocytes (CMs) promotes cardiac regeneration and mitigates pathological remodeling in mouse and pig MI models2,3. To precisely control YAP activity in vivo and encourage its clinical application, we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which triggers YAP activation in CMs upon exposure to a small molecule LMI070. One dose of LMI070 in mice induced a transient expression of active YAP (YAP5SA), which was subsequently degraded within a week. Consistent with earlier findings, YAP activation after injury improved cardiac function. Interestingly, administering a single LMI070 injection two weeks before MI provided lasting cardioprotection, which diminished by four weeks after the transient YAP activation, by reducing non-CMs cell death and enhancing cardiac function. Taken together, our novel gene therapy CM-YAPon presents a promising avenue for developing protective strategies against MI-induced cardiac injury. Overall design: AAV9 virus expressing YAPon was administrated to P7 ICR mice by intraperitoneal injection. At 6 weeks of age, animals were injected with DMSO or LMI070. Two weeks later, left anterior descending (LAD) ligation was performed ("MI") or sham surgery ("Sham"). Ventricular tissue below the suture was separated from the heart 7 days following surgery. Nuclei were collected using a Chromium Nuclei Isolation Kit and single nuclei RNA-sequencing was performed using the 10x Single Cell 3' Reagents.