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.

Figure 1

Direct and transvascular techniques of gene delivery. (a) Intramyocardial injection via the intracavitary catheter in right ventricle. (b) Intramyocardial injection via the intracavitary catheter in left ventricle. (c) Intramyocardial injection via the syringe. (d) Transvascular intracavitary delivery. (e) Transvascular nonselective intracoronary delivery with aortic cross-clamping. (f) Transvascular selective antegrade intracoronary delivery.

Figure 2

Different catheters and stent for transvascular intracoronary wall gene delivery.

Figure 3

Optimization of gene delivery technology.

Figure 4

Closed-loop recirculatory systems. (a) Cardiopulmonary bypass-based technology e.g., molecular cardiac surgery with recirculating delivery (MCARD). After initiating systemic bypass, the vent cannulas were placed into left and right ventricles and connected to the venous limb of the circuit. The arterial limb is connected to the coronary sinus catheter. After stopping the heart with cardioplegia, recirculation commences for 20min and then coronary circuit flashed. (b) Catheter-based technology (V-Focus). Coronary venous blood was drained from the coronary sinus. Following oxygenation the blood is returned to the left main coronary artery via a roller pump. Gene of interest was delivered into the antegrade limb of the circuit. Time of recirculation is 10min. To minimize systemic expression coronary venous blood collection continued for 2 min, and the blood was diverted to a drainage bag. Main differences between V-Focus and MCARD: (i) beating vs stopping heart; (ii) direction of recirculation (coronary arteries to coronary sinus vs coronary sinus to coronary arteries); (iii) time of recirculation (10 vs 20min); (iv) percutaneous catheter- based methodology vs cardiopulmonary bypass-based.

Figure 5

Schematic of pathways of retrograde gene delivery via coronary sinus.

Figure 6

(a) The movement of fluid between capillaries and the interstitial fluid. The direction of fluid with vector movement across the capillary wall depends on the difference between two opposing forces: hydrostatic and osmotic pressure. With retrograde perfusion, hydrostatic pressure increases at the venous end of the capillaries and therefore gene filtration and transduction are also increased. (b) Coronary capillary net. After the tissue has been perfused through the coronary sinus, capillaries join to become arterioles and metarterioles which return blood to the aorta. A capillary net consist of two types of vessels: true capillaries which provide exchange between cells and thoroughfare (shunts) channels which directly connects the arterioles and venules. Precapillary sphincters are rings of smooth muscles at the origin of arterial capillaries that regulate blood flow through a tissue. The advantage of the retrograde delivery is its ability to overcome the resistance of precapillary sphincters proximally located on the arterial side of the capillary bed. Thus, less blood is shunted through the thoroughfare channels into the cardiac chambers.