Novel gene therapy CM-YAPon protects the mouse heart from myocardial infarction - 3 day post-LMI

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. AAV9 virus expressing YAPon or saline was administrated to 6 week old adult mice by retro-orbital injection. Two weeks later, animals were injected with DMSO or LMI070. The apex of the ventricle was separated from the heart 3 days later. Nuclei were isolated from the apex tissue we collected for single nucleus RNA sequencing. Nuclei were collected using a Chromium Nuclei Isolation Kit (10x Genomics, PN-1000493). Single nuclei RNA-seq was performed using Single Cell 3′ Reagents Kit (10x Genomics, Chromium Next GEM Single Cell 3′ Kit version 3.1 or GEM-X Single Cell 3' Kit v4).