SERCA2a Gene Therapy in Heart Failure

Study Questions:

Does intracoronary gene therapy with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) improve outcomes in patients with heart failure?


CUPID 2 is a randomized, double-blind, placebo-controlled, phase 2b trial of 250 symptomatic heart failure patients with left ventricular ejection fractions of <35%. Patients were randomized to receive a single intracoronary infusion of 1 × 10¹³ DNase-resistant particles of AAV1/SERCA2a (n = 123) or placebo (n = 127). The primary endpoint was time to recurrent events (hospital admission because of heart failure or ambulatory treatment for worsening heart failure) with a median follow-up of 17.5 months.


Treatment with AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs. 128 events; hazard ratio, 0.93; 95% confidence interval, 0.53-1.65; p = 0.81). Approximately 16% of patients died in the placebo group and 21% of patients died in the AAV1/SERCA2a group.


The authors concluded that AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction.


Myocardial SERCA2a activity is reduced in subjects with heart failure, and preclinical studies have shown that myocardial function is improved with enhancement of SERCA2a activity. This current large gene therapy trial is a follow-up to a promising pilot study (CUPID 1) that demonstrated beneficial effects of SERCA2a gene therapy in patients with advanced heart failure. The authors suggest that one of the reasons for the negative results of the current study may be due to reduced transduction efficiency, as differences in the proportion of empty viral capsids were noted between the two studies. However, it is also possible that SERCA2a is not the right target in human heart failure. On a positive note, gene therapy with AAV1 may be feasible with other constructs considering no apparent safety issues emerged under these conditions.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Adenosine Triphosphatases, Endoplasmic Reticulum, Genetic Therapy, Heart Failure, Myocardium, Sarcoplasmic Reticulum, Stroke Volume, Up-Regulation

< Back to Listings