Percutaneous transluminal gene transfer into canine myocardium in vivo by replication-defective adenovirus

The aim was to examine the feasibility, efficiency and safety of adenovirus-mediated in vivo gene transfer into the canine myocardium by a percutaneous transluminal method using a needle-catheter.

Either a replication-defective adenovirus (Adex1SRLacZL) or a plasmid (pSRLacZ), both expressing E. coli lacZ coding beta-galactosidase (beta-gal), was directly injected into the left ventricle of dogs through a needle-catheter inserted via a femoral artery. Expression of lacZ was examined by histochemical staining and quantified by measuring beta-gal activity.

Injections with Adex1SRLacZL induced lacZ expression as a result of 40 out of 41 injections; the expression level was 10 times higher than that obtained with pSRLacZ. Induced beta-gal activity was detected within 24 h, peaked at 7 days and retained for 2 weeks after gene transfer. A repetitive administration of the same adenovirus at 14 days after the first injection also evoked a reduced but significant level of expression despite neutralizing antibodies to adenovirus in serum. Although injection induced an inflammatory response that peaked at 3 days after injection and gradually subsided without a second peak, the temporal change and the extent of inflammation induced by adenovirus injection was not significantly different from those induced by injection with either saline or plasmid. Neither leakage of enzymes such as CPK or LDH nor alteration in the ECG was detected in the 30 days following gene transfer.

Our findings demonstrate that a catheter-mediated direct injection with an adenovirus can induce gene expression in the ventricle more efficiently without additional myocardial damage and inflammation compared with injection with a plasmid. A repeat dose of the same adenovirus elicited gene expression at an attenuated but significant level. This method may potentially have clinical applications: in modifying myocardial phenotype and/or improving general circulation under certain circumstances.