Long Term Effects of AAV1/SERCA2a Gene Transfer in Patients with Severe Heart Failure: Analysis of Recurrent Cardiovascular Events and Mortality.

TitleLong Term Effects of AAV1/SERCA2a Gene Transfer in Patients with Severe Heart Failure: Analysis of Recurrent Cardiovascular Events and Mortality.
Publication TypeJournal Article
Year of Publication2013
AuthorsZsebo KM, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, Hajjar RJ
JournalCirculation research
Date Published2013 Sep 24
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 AAV1 vector carrying the cardiac sarcoplasmic reticulum ATPase pump (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of therapy at 12 months, and results were previously reported. Objective: To report long-term (3-year) clinical effects and transgene expression for 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 x 10(11) DNase Resistant Particles [DRP], middle dose-3 x 10(12) DRP and high dose-1 x 10(13) DRP) versus placebo. The following recurrent cardiovascular and terminal events were tracked over 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 pre-specified 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: Following a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure positive signals in terms of cardiovascular events persist for years.

DOI10.1371/journal.pone.0075464
Alternate JournalCirc. Res.