Molecular targets in heart failure gene therapy: current controversies and translational perspectives

Abstract

Gene therapy of heart failure is gaining momentum as a result of the recent successful completion of phase II of the CUPID trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing SERCA2a. Resorting to gene therapy allows the manipulation of molecular targets not presently amenable to pharmacologic modulation. This review focuses on the molecular targets of heart failure gene therapy that have demonstrated translational potential. At present, most of these targets are related to calcium handling in the cardiomyocyte. They include SERCA2a, phospholamban, the S100A1 protein, the ryanodine receptor and the inhibitor of the protein phosphatase 1. Other targets, related to cAMP signaling, are reviewed, such as adenylyl cyclase. microRNAs are emerging as novel therapeutic targets and convenient vectors for gene therapy, particularly in heart disease. We propose a discussion of recent advances and controversies in key molecular targets of heart failure gene therapy.

The Ubiquitin-Like SUMO System and Heart Function

“…107 Dysregulation of Ca 2+ cycling and reduction of SERCA2a activity represent hallmarks of heart failure and are recognized as major pathogenic drivers in diseased hearts. As reviewed extensively elsewhere, 6,107 Hajjar et al revealed that the levels of SUMO1 (but not SUMO2/3) are decreased in a murine heart failure model and that SERCA2a is critically and positively regulated by SUMO1 conjugation. 47 Identification and mutation of the 2 major SUMOylation sites in SERCA2a (K480R and K585R) revealed that loss of SUMOylation significantly decreases ATP-binding affinity and ATPase activity of SERCA2a, respectively.…”

“…Researchers have characterized changes in gene activity and posttranslational modifications (PTMs) of specific cardiac proteins, contributing to impaired cardiac contractility and promoting pathological mitochondrial or metabolic alterations. 6,7 However, very few new drugs have emerged from such efforts, despite a rising number of patients suffering from heart failure. It seems likely that the prevalence of heart insufficiency will further increase in the future because of an aging population and a prolonged lifespan of cardiac patients, which represents a pressing need to develop new therapeutic approaches.…”

Gene therapy, science fiction or science fact?

“…They were used in craniofacial regeneration [4,25] and in reprogramming differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cell structure and function [25]. Many other huge successes were achieved in several diseases such as corneal [7,26], retinal [27,28], cochlear [29], osteoarthritis [2,30], heart failure [31], and Parkinson's disease [32].…”

Molecular targets of current and prospective heart failure therapies

“…The functional remodelling is associated with alterations in the mRNA and protein expression and post-translational modification of a number of proteins involved in Ca 2+ signalling underlying excitation–contraction coupling 4. The extracellular matrix participates in the remodelling through the key process of myocardial fibrosis, which has also emerged as a therapeutic target in HF 9.…”