Heart failure is a leading cause of hospitalization in the US and Europe and its incidence continues to grow. This is because although treatments to open coronary arteries after myocardial infarction allow patients to survive longer, they eventually end up with additional myocardial damage. Added to that, an aging population is fuelling heart failure rates.
Celladon began the first human study of gene therapy in heart failure in 2007. The treatment, a genetically targeted enzyme replacement known as AAV1/SERCA2a, is designed to restore impaired calcium cycling—a hallmark of heart failure—and thus help maintain myocardial contractile function. Using the adeno-associated viral vector AAV1, Celladon's treatment delivers the gene encoding the sarcoplasmic reticulum CA2+ ATPase (SERCA2a) enzyme, a calcium transporter critical to maintaining calcium homeostasis, which is downregulated in heart failure. Positive results from the initial CUPID phase 1/2 study prompted the company to start enrolling patients in 2012 for the phase 2b CUPID2 clinical trial, which encompassed 250 patients across more than 50 centers in the US and Europe (J. Card. Fail. 15, 171–181, 2009). “A lot of us were very optimistic and hopeful that CUPID2 would meet its endpoint,” says Barry Greenberg of the University of California, San Diego (UCSD), who chaired the CUPID2 executive clinical steering committee. “There was a very logical and appropriate scientific rationale and the study was done very well,” he says. “But it just didn't work out.”
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