Cell-Based GATA4 Cardiac Gene Transfer Using Cell-Penetrating Peptide

Abstract

See related article, pages 1626–1633 Congestive heart failure (CHF) is the only cardiovascular disease that is increasing in prevalence.1 Patients with CHF who have symptoms with mild activity or at rest (Class III and Class IV) have a poor long-term outcome, with 5-year age-adjusted mortality of 50%.2,3 Heart transplantation has an 80% 5-year survival rate, but only 3000 cardiac transplants are performed in the US each year, where the prevalence for severe CHF is estimated at 5 million patients.4 Angiotensin converting enzyme inhibitors, aldosterone antagonists, β-adrenergic receptor antagonists, and implanted cardiac defibrillators have improved survival. However, even with optimal medical and device management, heart failure is an inexorable disease associated with unacceptably high morbidity and mortality.1 Because the prevalence of CHF is high and the outlook dismal, new therapeutic approaches are needed. In gene transfer experiments, one generally studies how increased expression of a single molecule influences signal transduction and cardiac function. These studies have identified a large number of potential therapeutic targets in cardiac myocytes, including cell membrane receptors and their ligands, calcium handling proteins, intracellular signaling molecules, transcription factors, and contractile proteins in cardiac myocytes.5–9 An abundance of therapeutic candidates is thwarted by the Achilles’ heel of cardiovascular gene transfer—the paucity of evidence for a vector and delivery method that will provide adequate cardiac expression safely. The exuberance engendered by cardiovascular gene therapy has subsided over the last 10 years, supplanted by similar hopes for cell-based therapy. Bone marrow–derived cells, endothelial progenitor cells, and embryonic or mesenchymal stem cells have been used successfully in animal models,10,11 although debate continues regarding cardiac myocyte regeneration per se.12 Clinical trials using bone marrow–derived cells in patients with acute …