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: Victor Kairouz, Larissa Lipskaia, Roger J Hajjar, Elie R Chemaly
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1254 Pg. 42-50 (Apr 2012) ISSN: 1749-6632 [Electronic] United States
• PMID: 22548568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2012 New York Academy of Sciences.

Chemical References

• CXCL12 protein, human
• Calcium-Binding Proteins
• Chemokine CXCL12
• MicroRNAs
• Ryanodine Receptor Calcium Release Channel
• S100 Proteins
• S100A1 protein
• SUMO-1 Protein
• SUMO1 protein, human
• phospholamban
• Cyclic AMP
• Protein Phosphatase 1
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium-Binding Proteins (metabolism)
• Chemokine CXCL12 (genetics)
• Cyclic AMP (metabolism)
• Genetic Therapy (methods, trends)
• Genetic Vectors
• Heart Failure (genetics, metabolism, therapy)
• Humans
• MicroRNAs (genetics, therapeutic use)
• Models, Cardiovascular
• Myocytes, Cardiac (metabolism)
• Protein Phosphatase 1 (antagonists & inhibitors, metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• S100 Proteins (metabolism)
• SUMO-1 Protein (metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (genetics, metabolism)
• Signal Transduction
• Translational Research, Biomedical