Cardiotropic AAV gene therapy for heart failure: a phase 1 trial

Innovative approaches for the treatment of heart failure are needed beyond conventional medical therapy to reverse ventricular dysfunction and modify the course of the disease. AB-1002, a chimeric cardiotropic adeno-associated viral vector that delivers constitutively active protein phosphatase 1 inhibitor 1 to cardiomyocytes, improves cardiac function in preclinical models of heart failure. Here we carried out a phase 1 study to evaluate the safety and feasibility of a single antegrade coronary artery infusion of AB-1002 in patients with nonischemic cardiomyopathy, New York Heart Association class III heart failure, and a left ventricular ejection fraction of 15–35%. Patients received 3.25 × 1013 viral genomes (cohort 1, n = 6) or 1.08 × 1014 viral genomes (cohort 2, n = 5). In total, nine men and two women were included in the study. No adverse events (AEs) or serious AEs were attributed by the investigators to the study treatment; most AEs were mild or moderate in severity. One death occurred, which was considered not to be related to the treatment with AB-1002. Self-limiting, mild, asymptomatic elevations in liver enzymes occurred, predominantly in cohort 2. The preliminary assessments of efficacy outcomes showed improvements in the New York Heart Association class and left ventricular ejection fraction in both cohorts and improvements in peak oxygen consumption and 6-min walk test performance in cohort 1. These results support the further assessment of AB-1002 in clinical trials. The ClinicalTrials.gov registration was NCT04179643 . In a phase 1 dose-escalation study including 11 patients with heart failure who were followed for 12 months, delivery of a cardiotropic adeno-associated viral vector designed to deliver constitutively active protein phosphatase 1 inhibitor 1 to the heart was well tolerated and showed preliminary evidence of efficacy.