Gene therapy in heart failure: the unexpected results from the CUPID 2 trial

Abstract

Heart failure is still a major cause of morbidity and mortality in Europe and North America. In the last three decades, gene therapy emerged as a target in the molecular mechanisms implicated in heart failure encouraging preclinical gene therapy studies in small and large animal models. Prior studies documented a decreased expression of sarcoplasmic reticulum Ca2+-ATPase protein (SERCA2a), a major cardiac calcium cycling protein, in heart failure. These results paved the way to preliminary studies based on gene transfer strategies of SERCA2a. The encouraging results in terms of safety and surrogate clinical endpoints led to a large randomized clinical study, the CUPID trial, including patients with heart failure and reduced ejection fraction. This phase IIb trial enrolling 250 patients randomized to intracoronary delivery of adeno-associated virus 1 (AAV1)/SERCA2a or placebo concluded with a non-superiority of the studied therapy, thus not confirming the results of the previous experiences with the same approach. In the present manuscript, we provide an overview of the scientific experiences that preceded the design of this major trial, then critically revising its structure and results. Finally we tried to understand the reasons of this unexpected failure and which are the future perspectives of gene therapy for heart failure.