Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation

Abstract

Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca(2+)-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality.

Keywords: Adeno-associated viral vector; Adenylate cyclase; CRISPR; Cardiovascular disease; Clinical trials; Gene therapy; Heart failure; S100A1; SERCA2a; miRNA.

Figure 1

Strategies to increase cardiac-specific gene transfer using AAV vectors using naturally occurring AAV serotypes, AAV capsid engineering, or directed molecular evolution and in vivo selection of cardiotropic AAV variants (see text for details). The relative cardiac transduction efficiency of the naturally occurring AAV serotypes (AAV2, AAV1, AAV6, AAV8, and AAV9) based on preclinical murine studies is shown schematically.

Figure 2

Angiogenic factors in gene therapy for CVD. Description of the membrane receptor involved in the angiogenic factor pathways and the physiological effects. VEGF-A¹⁶⁵, vascular endothelial growth factor; FGF-4, fibroblast growth factor 4; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor.