AAV-mediated gene therapy for heart failure: enhancing contractility and calcium handling.

Heart failure is a progressive, debilitating disease that is characterized by inadequate contractility of the heart. With an aging population, the incidence and economic burden of managing heart failure are anticipated to increase substantially. Drugs for heart failure only slow its progression and offer no cure. However, results of recent clinical trials using recombinant adeno-associated virus (AAV) gene delivery offer the promise, for the first time, that heart failure can be reversed. The strategy is to improve contractility of cardiac muscle cells by enhancing their ability to store calcium through increased expression of the sarco(endo)plasmic reticulum Ca(2+)-ATPase pump (SERCA2a). Preclinical trials have also identified other proteins involved in calcium cycling in cardiac muscle that are promising targets for gene therapy in heart failure, including the following: protein phosphatase 1, adenylyl cyclase 6, G-protein-coupled receptor kinase 2, phospholamban, SUMO1, and S100A1. These preclinical and clinical trials represent a "quiet revolution" that may end up being one of the most significant and remarkable breakthroughs in modern medical practice. Of course, a number of uncertainties remain, including the long-term utility and wisdom of improving the contractile performance of "sick" muscle cells. In this regard, gene therapy may turn out to be a way of buying additional time for actual cardiac regeneration to occur using cardiac stem cells or induced pluripotent stem cells.