Introducing Genes to the Heart: All About Delivery.

Abstract

Recent clinical gene therapy trials for the treatment of heart failure (HF) have failed to meet primary efficacy end points and have tampered enthusiasm for the future application of cardiac gene therapy. These results have brought to light the difficulty of efficiently introducing genes into the human heart and have focused on potential problems that need to be addressed before further clinical applications. These trials, however, have established the safety of gene delivery vectors for cardiac targeting in humans. The sinusoidal trajectory of gene therapy continues, and despite these setbacks, the future of the field is promising. In the past year, the results of 3 recent phase II clinical gene therapy trials targeting HF became available.1–3 These serial publications, however, all failed to meet primary efficacy end points. In the CUPID IIb trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b), the efficacy of intracoronary-administered recombinant adeno-associated virus (AAV) carrying sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) at a dose of 1×1013 DNase-resistant particles was examined in 250 patients.1 In contrast to a significant reduction of clinical events in the phase I/IIa trial, the number of adverse events in this trial was similar between the treated and the control groups. The STOP-HF trial (Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Heart Failure) examined the efficacy of endocardial direct injection of plasmid stem cell–derived factor-1 with doses of 15 and 30 mg in 93 patients.2 The primary end point was a composite score of a 6-minute walk distance and a quality-of-life questionnaire. This study again reported similar outcomes in primary end points between the treated and the control groups. The most recent report was the trial of adenovirus 5–mediated adenylyl cyclase 6 gene therapy using intracoronary delivery in 56 patients. …