Although pharmacologic therapies have provided gains in reducing the mortality 
of heart failure, the rising incidence of the disease requires new approaches to 
combat its health burden. Twenty-five years ago, abnormal calcium cycling was 
identified as a characteristic of failing human myocardium. Sarcoplasmic 
reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was 
found to be a key factor in the alteration of calcium cycling. With the 
advancement of gene vectors, SERCA2a emerged as an attractive clinical target 
for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a 
upregulation has been found to improve myocardial function in animal models. The 
clinical benefits of overexpressing SERCA2a have been demonstrated in the phase 
I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in 
Cardiac Disease (CUPID). This study has demonstrated that a persistent 
expression of the transgene SERCA2a is associated with a significant improvement 
in associated biochemical alterations and clinical symptoms of heart failure. In 
the coming years, additional targets will likely emerge that are amenable to 
genetic manipulations along with the development of more advanced vector systems 
with safer delivery approaches.