title: Molecular targets in heart failure gene therapy: current controversies and translational perspectives.
abstract: Use of gene therapy for heart failure is gaining momentum as a result of the recent successful completion of phase II of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a). Resorting to gene therapy allows the manipulation of molecular targets not presently amenable to pharmacologic modulation. This short 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, S100A1, 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.
authors.affiliation: Department of Internal Medicine, University at Buffalo School of Medicine and Biomedical Sciences, Erie County Medical Center, Buffalo, New York.
authors.forename: Victor
authors.initials: V
authors.lastname: Kairouz
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York.
authors.forename: Elie R
authors.initials: ER
authors.lastname: Chemaly
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005822:Genetic Vectors; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D057170:Translational Research, Biomedical; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D054377:Chemokine CXCL12; D000242:Cyclic AMP; D035683:MicroRNAs; D054645:Protein Phosphatase 1; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; D025842:SUMO-1 Protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C515255:CXCL12 protein, human; C110294:S100A1 protein; C495501:SUMO1 protein, human