Gene therapy targeted at calcium handling as an approach to the treatment of heart failure

• Published in: Pharmacology & therapeutics (Oxford) Vol. 105; no. 3; pp. 211 - 228
• Main Author: Hoshijima, Masahiko
• Format: Journal Article
• Language: English
• Published: England 01.03.2005
• Subjects: Calcium - metabolism; Calcium-Transporting ATPases - metabolism; Genetic Therapy - methods; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - therapy; Humans; Sarcoplasmic Reticulum Calcium-Transporting ATPases
• ISSN: 0163-7258
• DOI: 10.1016/j.pharmthera.2004.10.006

Chronic congestive heart failure primarily of ischemic origin remains a leading cause of morbidity and mortality in the United States and other leading countries. The current main stream of therapy is, however, palliative and uses a complex regimen of drugs, the actions of which are not understood completely. On the other hand, unfavorable remodeling after cardiac injuries of multiple causes has been thought to lead to cardiac contractile dysfunction in heart failure, and a body of scientific evidence points to a central role of intrinsic defects in intracellular calcium handling in cardiomyocytes that arise from the distorted functions of several key regulatory molecules on plasma membrane or sarcoplasmic reticulum (SR), a muscle-specific intracellular membrane complex that stores calcium at high concentration. Accordingly, the initial appetite to use gene transfer strategies to modulate calcium regulatory proteins was to validate molecular targets for the development of new pharmaceuticals; however, remarkable therapeutic efficacies found in an initial series of studies using various heart failure animal models immediately promoted us to seek ways to directly apply gene transfer to cure clinical heart failure. The first part of this article reviews our up-to-date knowledge of various functional components to regulate calcium handling in cardiomyocytes, including beta-adrenergic receptor, L-type calcium channel, ryanodine receptor (RyR) and its associated proteins, sarco-endoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLN), and their abnormalities in failing hearts. A series of new somatic gene transfer attempts targeting calcium handling in cardiomyocytes are discussed thereafter.