The first clinical trial of gene therapy in patients with HF was launched in the United States in 2007 (77- 78). CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) is a multicenter trial designed to evaluate the safety profile and the biological effects of gene transfer of the SERCA2a cDNA by delivering a recombinant AAV1 (AAV1.SERCA2a) in patients with advanced HF. Participants in this trial were administered a single intracoronary infusion of AAV1.SERCA2a using an open-label approach (77- 78). Cohorts 1 to 4 of 3 patients each received sequentially a single increasing dose of AAV1.SERCA2a. The 12-month follow-up of these patients showed an acceptable safety profile (77- 78). Improvement was detected in several patients, reflected by symptomatic (n = 5), functional (n = 4), biomarker (n = 2), and LV function/remodeling (n = 6) parameters. Although this was a phase 1 study involving a small number of patients, early results found that AAV1.SERCA2a treatment conferred a quantitative biological benefit. In the phase 2 trial, 39 patients with advanced HF were randomized to receive intracoronary AAV1-mediated SERCA2a gene delivery (in 1 of 3 doses: low dose, 6 × 1011 DNAse-resistant particles; middle dose, 3 × 1012 DNAse-resistant particles; and high dose, 1 × 1013 DNAse-resistant particles) versus placebo. Patient's symptoms (New York Heart Association functional class, Minnesota Living With Heart Failure Questionnaire, functional status [6-min walk test, and Vo2max]), N-terminal pro–B-type natriuretic peptide levels, and echocardiographic measures were evaluated over 6 months. Treatment success was determined by examining concordant trends in these end points for group- and patient-based comparisons as well as clinical outcomes. The AAV1.SERCA2a high-dose group met the prespecified criteria for success at the group and individual patient levels. AAV1.SERCA2a-treated patients, versus placebo, demonstrated improvement or stabilization in New York Heart Association functional class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, Vo2max, N-terminal pro–B-type natriuretic peptide levels, and LV end-systolic volumes. Significant increases in time to adjudicated cardiovascular events and a decreased frequency of cardiovascular events per patient were observed in all patients receiving AAV1.SERCA2a. No increases in adverse events, disease-related events, laboratory abnormalities, or arrhythmias were observed in AAV1.SERCA2a-treated patients compared with those receiving placebo.