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

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, 6×10(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.

• Authors: Krisztina Zsebo, Alex Yaroshinsky, Jeffrey J Rudy, Kim Wagner, Barry Greenberg, Mariell Jessup, Roger J Hajjar
• Journal: Circulation research (Circ Res) Vol. 114 Issue 1 Pg. 101-8 (Jan 03 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 24065463 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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