(F1262) MODULATION OF SERCA2A OF INTRA-MYOCYTIC CALCIUM TRAFFICKING IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION (MUSIC-HFREF) AND STEM CELL MODELS OF HEART FAILURE
Abstract: Patients with Heart Failure with reduced Ejection Fraction (HFrEF) continue to experience high morbidity and mortality. A critical characteristic of failing hearts is abnormal intracellular Ca2+ handling, which is due to a decrease in expression and function of the cardiac sarcoplasmic reticulum calcium ATPase pump (SERCA2a). Delivery of an adeno-associated type 1 vector carrying SERCA2a (AAV1.SERCA2a) improved contractile function in a dose dependent manner in many animal studies, and also in dose optimization studies using human stem cell-based engineered mini-heart tissue models of heart failure (HF). In patients, low doses were safe but led to marginal outcomes due to poor myocardial transduction. Through a local intracoronary delivery, we have titrated to a dosage high enough for efficacy without causing immunogenicity or adverse events, and when normalized by cardiomyocyte number, the estimated dose per cell is consistent with the optimal range obtained with the mini-heart models in vitro. Compared to earlier trials, our ongoing phase 1/2a clinical trial for the treatment of HFrEF (MUSIC-HFrEF) delivers higher doses of AAV1.SERCA2a (3E13 viral genome(vg)/patient and 4.5 E13 vg/patient) through intracoronary infusion in both ischemic and non-ischemic patients with left ventricular ejection fraction (LVEF) of 35% or less. To date six patients have received a dose of 3E13 vg/patient of AAV1.SERCA2a and two patients received 4.5E13 vg/patient, and the follow-up period has been 1 to 26 months. There have been no gene therapy or procedure‒related serious adverse events at both doses post-injection. Four of the six patients in the 3E13vg/patient dose have shown improvements in NYHA HF classification at 6 and 12 months. Clinically meaningful improvements have been observed in LVEF and 6-minute walk test (6MWT), along with decreases in HF biomarkers NT-Pro-BNP and troponin I. Based on the early clinical efficacy at a dose of 3E13vg/patient of AAV1.SERCA2a, the enrollment of patients at a higher dose of 4.5E13 vg/patient is continuing. These encouraging results of high-dose AAV1.SERCA2a in patients with HFrEF (ischemic and non-ischemic) not observed previously may offer alternative treatments to patients with severe heart failure where a large medical unmet need remains.
