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

Krisztina Zsebo, Alex Yaroshinsky, Jeffrey J. Rudy, Kim Wagner, Barry Greenberg, Mariell Jessup, Roger J. Hajjar

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

Abstract

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, 6×1011 DNase-resistant particles; mid-dose, 3×10 12 DNase-resistant particles; and high-dose, 1×1013 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.

Original languageEnglish
Pages (from-to)101-108
Number of pages8
JournalCirculation Research
Volume114
Issue number1
DOIs
StatePublished - 3 Jan 2014

Keywords

  • clinical trial
  • genetic therapy
  • heart failure
  • sarcoplasmic reticulum calcium-transporting ATPases

Fingerprint

Dive into the research topics of 'Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: Analysis of recurrent cardiovascular events and mortality'. Together they form a unique fingerprint.

Cite this