Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins

Abstract

Catheter-based percutaneous transluminal gene delivery (PTGD) into the coronary artery still falls behind the expectations of an efficient myocardial gene delivery system. In this study gene delivery was applied by selective pressureregulated retroinfusion through the coronary veins to prolong adhesion of replication defective adenovirus within the targeted myocardium. Adenoviral vectors consisted either of luciferase (Ad.rsv-Luc) or ␤-galactosidase (Ad.rsv-␤Gal) reporter gene under control of an unspecific promotor derived from the Rous sarcoma virus (RSV). In this pig model, selective retrograde gene delivery into the anterior cardiac vein during a brief period of ischemia substantially

Retroinfusion of NFκB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs

“…In contrast, targeted retrograde delivery of DNA into ischemic myocardium has been successfully used in a previous preclinical study in pigs, providing a 50-fold higher transfection efficacy than antegrade intracoronary transfection. 17 Interestingly, in the present study retroinfusion of the liposome-decoy ODN at the end of the ischemic period sufficed to induce a sustained, though modest cardioprotective effect in our pig model. This effect could be increased by additional CD18 blockade, indicating an independent contribution of acute and subacute endothelial activation to myocardial ischemia/reperfusion injury.…”

“…We took advantage of a novel percutaneous transluminal retrograde gene delivery system to target NF B decoy oligonucleotides to the ischemic myocardium. 17 Whereas untreated control hearts displayed a substantial increase in NF Bbinding activation and leukocyte recruitment after 1 day of reperfusion, NF B inhibition by transfection of a suitable decoy ODN (see Figure 1c and d) reduced transcription of proinflammatory proteins (Figure 2), as well as leukocyte influx (Figure 3) and infarct size (Figure 5a) at 24 h of reperfusion. Because reversible reperfusion injury such as myocardial stunning might occur at 24 h of reperfusion, assessment of stable residual myocardial viability and function was performed after 7 days of reperfusion.…”

“…Recently, we demonstrated that myocardial reporter gene expression was 50-fold enhanced after retroinfusion using the coronary vein for delivery compared with intracoronary arterial injection. 17 In this study, selective pressure-regulated retroinfusion into a coronary vein (AIV) was performed during occlusion of the corresponding coronary artery (LAD), mimicking the clinical setting of coronary occlusion and recanalization. Using this catheter-based approach, we now infused liposomes carrying NF B ODN into the ischemic myocardium with or without systemic infusion of a CD18 antibody.…”

“…For this purpose, we infused NF B decoy ODN containing liposomes retrogradely into the vein draining the ischemic area, adjusting the retroinfusion pressure to the individual coronary venous anatomy. 17 With this approach, a significant portion of endothelial cells in the targeted area at risk were transfected with ODN 24 h after ischemia, whereas no transfection occurred in the control area (Figure 1b). After 7 days of reperfusion, no ODN was detectable in the area at risk.…”

“…After assessment of the individual occlusion pressure of the venous system, retroinfusion pressure was set 20 mmHg above the latter. After 55 min of ischemia, continuous pressure regulated retroinfusion 17 of isothermic Nacl 0.9% (20 ml/min) without or with separate, reflux valve-protected infusion of liposomes containing NF B decoy or scrambled ODN was conducted. At 60 min, retroinfusion was stopped and suction of the vein was performed for 30 s to prevent ODN dissemination.…”