Online Issues

Journal Vol 50 (2)

Gene Therapy in Large Animal Models of Human Cardiovascular Genetic Disease

Meg M. Sleeper, Lawrence T. Bish, and H. Lee Sweeney

Meg Sleeper, VMD, is an associate professor of cardiology in the Department of Clinical Studies at the University of Pennsylvania Veterinary School; Lawrence T. Bish, BA, is a PhD/MD student and H. Lee Sweeney, PhD, is Chair and professor of Physiology in the Department of Physiology at the University of Pennsylvania School of Medicine, all in Philadelphia.

Address correspondence and reprint requests to Dr. Meg Sleeper, Section of Cardiology, Department of Clinical Studies, MJR-VHUP, 3900 Delancey Street, Philadelphia, PA 19104 or email sleeper@vet.upenn.edu.

Abstract

Several naturally occurring animal models for human genetic heart diseases offer an excellent opportunity to evaluate potential novel therapies, including gene therapy. Some of these diseases—especially those that result in a structural defect during development (e.g., patent ductus arteriosus, pulmonic stenosis)—would likely be difficult to treat with a therapeutic gene transfer approach. However, the ability to transduce a significant proportion of the myocardial cells should make the various forms of inherited cardiomyopathy amenable to a therapeutic gene transfer approach. Adeno-associated virus may be the ideal vector for cardiac gene therapy since its low immunogenicity allows for stable transgene expression, a crucial factor when considering treatment of a chronic disease. Cardiomyopathies are a major cause of morbidity and mortality in both children and adults, and large animal models are available for the major forms of inherited cardiomyopathy (dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy). One of these animal models, juvenile dilated cardiomyopathy of Portuguese water dogs, offers an effective means to assess the efficacy of therapeutic gene transfer to alter the course of cardiomyopathy and heart failure. Correction of the abnormal metabolic processes that occur with heart failure (e.g., calcium metabolism, apoptosis) could normalize diseased myocardial function. Gene therapy may offer a promising new approach for the treatment of cardiac disease in both veterinary and human clinical settings.

Key Words: calcium metabolism; cardiomyopathy; dog model; gene transfer; heart disease; heart failure; large animal model