Gene delivery technologies for cardiac applications

Abstract

Ischemic heart disease (IHD) and heart failure (HF) are major causes of morbidity and mortality in the Western society. Advances in understanding the molecular pathology of these diseases, the evolution of vector technology, as well as defining the targets for therapeutic interventions has placed these conditions within the reach of gene-based therapy. One of the cornerstones of limiting the effectiveness of gene therapy is the establishment of clinically relevant methods of genetic transfer. Recently there have been advances in direct and transvascular gene delivery methods with the use of new technologies. Current research efforts in IHD are focused primarily on the stimulation of angiogenesis, modify the coronary vascular environment and improve endothelial function with localized gene-eluting catheters and stents. In contrast to standard IHD treatments, gene therapy in HF primarily targets inhibition of apoptosis, reduction in adverse remodeling and increase in contractility through global cardiomyocyte transduction for maximal efficacy. This article will review a variety of gene-transfer strategies in models of coronary artery disease and HF and discuss the relative success of these strategies in improving the efficiency of vector-mediated cardiac gene delivery.

Myocardial Gene Transfer: Routes and Devices for Regulation of Transgene Expression by Modulation of Cellular Permeability

“…Retrograde gene delivery changes the hydrostatic and osmotic pressure, thereby increasing the capillary filtration ratio in the venous part of the capillary bed. Another advantage is the ability to overcome the resistance of precapillary sphincters located before arterial capillaries (Katz et al, 2012).…”

Surgical Methods for Cardiac Gene Transfer

“…Pressure regulated retrograde infusion into the anterior cardiac vein substantially increases gene expression in the targeted territory due to increased coronary passage time of more than tenfold compared with other methods [18]. Another advantage is an increased capillary filtration ratio in the venous part of the capillary bed and the ability to overcome the resistance of precapillary sphincters located before arterial capillaries [19]. However, one of the most serious shortcomings of single pass transvascular gene transfer is the very fast dilution of vector concentration in the circulating blood with subsequent gene and vector dissemination to collateral organs.…”

The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

“…First, it can be easily applied to clinical practice, particularly in patients with severe coronary artery disease. Second, it allows for prolonged adhesion time of the vector to the cardiac endothelium [46], and overcomes the resistance of precapillary sphincters proximally located on the arterial side of the capillary bed [47]. Finally, it can reduce myocardial reperfusion injury [48].…”