1. ¹Department of Hepatology and Transplantation, King's College London School of Medicine, James Black Centre, London, UK
2. ²Department of Clinical Perfusion Sciences, King's College Hospital, Denmark Hill, London, UK
3. ³Department of Cardiology, King's College London School of Medicine, James Black Centre, London, UK
4. ⁴Department of Women's and Children's Health, Paediatric Hepatobiliary Surgery, King's College Hospital, Denmark Hill, London, UK
5. ⁵Liver Transplantation and Hepatobiliary Surgery Service, Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK

Correspondence: Professor JW Fabre, Department of Hepatology and Transplantation, King's College London School of Medicine, James Black Centre, 123 Coldharbour Lane, London SE5 9NU, UK. E-mail: john.fabre@kcl.ac.uk

⁶These authors contributed equally to this work.

Received 14 August 2007; Revised 8 October 2007; Accepted 9 October 2007; Published online 15 November 2007.

Abstract

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 4 times higher than in rodents, but levels of gene delivery were 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.