Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava.
Hydrodynamic gene delivery is an attractive option for non-viral liver gene therapy, but requires evaluation of efficacy, safety and clinically applicable techniques in large animal models. We have evaluated retrograde delivery of DNA to the whole liver via the isolated segment of inferior vena cava (IVC) draining the hepatic veins. Pigs (18-20 kg weight) were given the pGL3 plasmid via two programmable syringe pumps in parallel. Volumes corresponding to 2% of body weight (360-400 ml) were delivered at 100 ml s(-1) via a Y connector. The IVC segment pressure, portal venous pressure, arterial pressure, electrocardiogram (ECG) and pulse were monitored. Concurrent studies were performed in rats for interspecies comparisons. The hydrodynamic procedure generated intrahepatic vascular pressures of 101-126 mm Hg, which is approximately 4 times higher than in rodents, but levels of gene delivery were approximately 200-fold lower. Suprahepatic IVC clamping caused a fall in arterial pressure, with the development of ECG signs of myocardial ischaemia, but these abnormalities resolved rapidly. The IVC segment approach is a clinically acceptable approach to liver gene therapy. However, it is less effective in pigs than in rodents, possibly because of larger liver size or a less compliant connective tissue framework.
Fabre
J W
JW
Department of Hepatology and Transplantation, King's College London School of Medicine, James Black Centre, London, UK. john.fabre@kcl.ac.uk
Grehan
A
A
Whitehorne
M
M
Sawyer
G J
GJ
Dong
X
X
Salehi
S
S
Eckley
L
L
Zhang
X
X
Seddon
M
M
Shah
A M
AM
Davenport
M
M
Rela
M
M
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage*; D005260:Female; D005471:Fluoroscopy; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000628:therapy*; D008156:Luciferases / Q000235:genetics; D023421:Models, Animal; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine; D014682:Vena Cava, Inferior; D014690:Venous Pressure
D004247:DNA; D008156:Luciferases