Gene Therapy for Coronary Artery Disease

Abstract

Congestive heart failure is the common end point for advanced coronary artery disease and the leading cause of mortality from heart disease. Stents and surgical bypass can address focal obstruction in larger coronary arteries, but diffuse small vessel disease is not amenable to these interventions. Intrinsic recovery is also limited, as adult cardiac muscle does not effectively regenerate after cardiomyocyte death. Cardiac gene therapy uses growth factors, genes or small molecules to alter gene expression for myocardial regeneration. Genes may be used to induce angiogenesis, reduce pathologic fibrosis, induce replication of endogenous cardiomyocytes, or expand existing cardiac progenitor cells into various cardiac subtypes. Delivery options include plasmids, integrative or non-integrative viruses, micro RNA or small molecules. Administration may be achieved systemically or by intracoronary or local injection, although local administration appears to provide key pharmacokinetic advantages. Initial attempts focused on creating new branches from existing blood vessels, often using vascular endothelial growth factor (VEGF). These demonstrated equivocal clinical results due, in part, to inconsistent study design, controls and clinically relevant endpoints as well as incomplete pharmacokinetics data on required gene “dose” or the ideal methods of gene delivery. Early lessons informed the development of cardiac cellular reprogramming, which transforms cardiac fibroblasts into induced cardiomyocytes using defined reprogramming factor cocktails. This approach has delivered improved post-infarct ejection fraction and reduced fibrosis in preclinical models. Gene therapy in cardiac disease is not yet ready for clinical application, but holds great promise for filling an important therapeutic gap in a growing patient population.