How to optimize in vivo gene transfer to cardiac myocytes: Mechanical or pharmacological procedures?

An efficient gene delivery system is a prerequisite for myocardial gene the rapy. Among the various procedures studied so far, catheter-based percutane ous gene delivery to the myocardium through the coronary vessels seems the most relevant to routine clinical practice; however, the optimal conditions remain to be determined. We selectively infused adenoviral vectors encodin g luciferase (1 x 10(9) PFU) or beta -galactosidase (1 x 10(10) PFU) into c oronary arteries of adult rabbits in various experimental conditions. Coron ary artery occlusion for 30 sec, during and after adenovirus delivery, was required to observe luciferase activity in the target area of the circumfle x artery (4.0 +/- 1.0 x 10(5) vs. 1.1 +/- 0.2 x 10(4) RLU/mg with and witho ut coronary occlusion, respectively, p<0.01, and 1.0 +/- 0.1 x 10(3) RLU/mg using nonselective infusion). When adenoviruses were delivered using high- pressure infusion (82 +/- 12 vs. 415 +/- 25 mmHg before and during infusion , respectively, p< 0.01), luciferase activity increased to 8.5 +/- 2.5 x 10 (5) RLU/mg (p< 0.05 vs coronary occlusion alone). Coronary venous sinus occ lusion with saline buffer retroinfusion starting before and during anterogr ade adenovirus delivery resulted in a further 4.7-fold increase in lucifera se activity (4.4 +/- 0.8 x 10(6) RLU/mg, p< 0.01) with 5-25% blue-stained m yocytes in the target area, compared with 0-5% with the other procedures. H istamine or VEGF-A(165) pretreatment, used to increase vascular permeabilit y, slightly increased gene transfer efficiency (8.5 +/- 2.0 x 10(5) and 9.0 +/- 2.5 x 10(5) RLU/mg respectively, p< 0.05 vs. coronary occlusion alone) . We conclude that catheter-mediated adenoviral gene transfer to cardiac my ocytes through coronary vessels can be a very efficient procedure for myoca rdial gene therapy, particularly when the vector residence time and perfusi on pressure in the vessels are increased.