Study Assessing Left Ventricular Administration of a Genetic Medicine Directing Organ Regeneration in Heart Failure

This Phase I, single-center, open-label, dose-escalation trial evaluates the safety, tolerability, and preliminary efficacy of YAP101 in adults with ischemic heart failure and reduced ejection fraction (HFrEF). YAP101, a novel gene therapy, delivers adeno-associated virus with a cardiomyocyte-specific promoter to express short hairpin RNAs (shRNAs) targeting Salvador 1 (SAV1), a key regulator of the Hippo signaling pathway. By transiently suppressing this pathway, YAP101 aims to induce cardiomyocyte regeneration, reduce fibrosis, and improve myocardial function. Eligible subjects will undergo a one-time transendocardial injection of YAP101 at one of three dose levels (5.0e12, 1.0e13, or 5.0e13 viral genomes/subject) using an investigational cardiac injection catheter. Following administration, subjects will be monitored for safety and functional outcomes through a series of outpatient visits over 12 months. Primary endpoints include the incidence of dose-limiting toxicities, adverse events, and the determination of the maximum tolerated dose (MTD). Secondary endpoints include changes in cardiac function assessed via MRI, biomarkers, exercise tolerance, and quality of life metrics. Safety will be overseen by an independent Safety Review Team (SRT), which will assess data before dose escalation. The study employs a 3+3 dose-escalation design to identify the MTD while minimizing risks. Subjects who complete the study will have the option to enroll in a long-term follow-up study for up to 5 years. The trial addresses the significant unmet need for regenerative therapies in heart failure, leveraging preclinical evidence of efficacy and safety. YAP101 has shown promising results in animal models, improving cardiac function, reducing fibrosis, and enhancing myocardial repair without significant adverse effects.