It is never too late for native cardiac repair: can genes awake the Sleeping Beauty in chronic patients?

Chronic heart failure (CHF), mainly caused by ischemic heart disease (IHD), represents the leading cause of disability and death in developed countries. The current standard of care does not provide a definitive solution for this condition, except for cardiac transplantation, which is hampered by the scarcity of organs and by rejection. Thus there is a compelling need for innovation in this field, in which regenerative medicine has emerged as the most promising hope for millions of patients worldwide. In this issue of the European Heart Journal, Chung and collegues report the results of a double-blind phase II clinical trial to assess the safety and efficacy of plasmid stromal cell-derived factor-1 (pSDF-1) in patients with CHF. Ninety-three patients with end-stage IHD were randomized 1:1:1 to receive transendocardial injections of 15 mg or 30 mg of pSDF-1 or placebo. The primary endpoint was a composite of 6-min walk distance and quality of life [Minnesota Living with Heart Failure Questionnaire (MLWHFQ)] at 4 months, which was safely improved in the high-dose group. This clinical benefit was extended to 12-months follow-up and was accompanied by improvements in ventricular remodelling, especially in those patients with the most severe ventricular dysfunction. The Screening to Prevent Heart Failure (STOP-HF) trial constitutes an important breakthrough in the field of cardiac repair, demonstrating for the first time the safety and clinical benefits of plasmid DNA administration in CHF patients. Like in the only published phase II gene therapy trial to date, very sick patients on optimal treatment were included (median ejection fraction 29% due to 10-year-old scars), representing the most challenging population for cardiac repair, since cardiac cells are lost and extracellular matrix is definitely disassembled. Chung and colleagues demonstrate that the activation of the SDF-1–CXCR4 axis is possible even in these advanced stages of IHD with evident clinical benefits. The SDF-1– CXCR4 axis orchestrates stem cell homing into the myocardium after ST-segment elevation myocardial infarction, but only for a few days after the ischemic event. It also plays a role in the adverse ventricular remodelling process, having anti-apoptotic effects, inducing angiogenesis, inhibiting fibrosis and improving contractility in the scar border zone (Figure 1). – 6 What is somehow impressive is that gene therapy is able to reactivate native cardiac repair mechanisms in a completely unstructured tissue, promoting the expression of stem cell homing signals otherwise no longer found. This observation by itself justifies further investigations in the form of phase III clinical trials. The first era of myocardial regeneration, mainly based on stem cell delivery into the injured myocardium, changed the dogma of the non-reparative potential of the heart, brought physicians closer to cardiac biology and allowed us to understand the intricate network of molecular and cellular healing processes that could be therapeutically modified after an ischemic insult to prevent CHF. However, this ‘stem cell–based’ approach has been proved ineffective to repair the heart in advanced phases of IHD. Therefore, along with promising advances in cell-based tissue engineering, new types of ‘non-cellular’ regenerative treatments are being explored. Among them, the manipulation of the genetic material that governs cardiac cell function is the most realistic. Gene therapy is defined as the technology by which genes, small DNA or RNA molecules are delivered to a target cell or organ to treat or to prevent diseases. Sequencing of the human genome and new developments in the field of gene transfer vectors have provided us with the necessary tools to target specific genes that determine cardiac diseases. Since the first clinical trial in 1998,