Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality

Circ Res. 2014 Jan 3;114(1):101-8. doi: 10.1161/CIRCRESAHA.113.302421. Epub 2013 Sep 24.


Rationale: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using an adeno-associated virus serotype 1 (AAV1) vector carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of the therapy at 12 months, and results were previously reported.

Objective: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1.

Methods and results: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6×10(11) DNase-resistant particles; mid-dose, 3×10(12) DNase-resistant particles; and high-dose, 1×10(13) DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low- and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up.

Conclusions: After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years.

Keywords: clinical trial; genetic therapy; heart failure; sarcoplasmic reticulum calcium-transporting ATPases.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Dependovirus / genetics
  • Double-Blind Method
  • Female
  • Genetic Therapy*
  • Genetic Vectors / genetics
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics*
  • Time
  • Transgenes / genetics
  • Treatment Outcome


  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human