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


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.
From the Celladon Corporation, San Diego, CA (K.Z., J.J.R., K.W.); AY Statistical Consulting, San Andreas, CA (A.Y.); The University of California, San Diego Medical Center, La Jolla (B.G.); Penn Heart and Vascular Center, Hospital of the University of Pennsylvania, Philadelphia (M.J.); and Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (R.J.H.).
Krisztina
K
Zsebo
Alex
A
Yaroshinsky
Jeffrey J
JJ
Rudy
Kim
K
Wagner
Barry
B
Greenberg
Mariell
M
Jessup
Roger J
RJ
Hajjar
D000328:Adult; D000368:Aged; D000229:Dependovirus / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006333:Heart Failure / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D013995:Time; D019076:Transgenes / Q000235:genetics; D016896:Treatment Outcome
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human
clinical trial; genetic therapy; heart failure; sarcoplasmic reticulum calcium-transporting ATPases