AAV-S100A1

**AAV-S100A1** is an investigational adeno-associated virus (AAV)-based gene therapy designed to treat heart failure by delivering the S100A1 gene to cardiac myocytes. S100A1, a Ca2+-binding protein depleted in failing hearts, enhances myocardial contractility by improving sarcoplasmic reticulum (SR) Ca2+ handling: it boosts SERCA2a-mediated Ca2+ uptake, reduces SR Ca2+ leak, increases fractional SR Ca2+ release via RyR2 modulation, and optimizes sarcomeric compliance and mitochondrial energy supply. Preclinical studies in rodent and large animal models of post-ischemic heart failure demonstrate restored contractile function, reversed remodeling, improved survival (e.g., 90% one-year survival in animal HF models), and normalized Ca2+ transients without safety issues; uniQure acquired InoCard's program in 2015, planning first-in-human trials in 2016, though no recent clinical progress is confirmed.