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Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava

Gene Therapy volume 15, pages 452–462 (2008)Cite this article

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.

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Acknowledgements

This work was funded by the UK Department of Health and the Welton Foundation. We would like to thank Mr Peter Matthews of Medrad for generously providing the syringe pumps, Mr Chris Blacklock of Chalice Medical for advice on pumps, Mr Steve Clarke of Kimal for advice on catheters and high pressure tubing, and Dr Roy Sherwood, Department of Clinical Biochemistry, King's College Hospital, London, for performing the liver function tests.

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Author notes

  1. M Davenport and M Rela: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatology and Transplantation, King's College London School of Medicine, James Black Centre, London, UK

    J W Fabre, G J Sawyer, X Dong, S Salehi, L Eckley & X Zhang

  2. Department of Clinical Perfusion Sciences, King's College Hospital, Denmark Hill, London, UK

    A Grehan & M Whitehorne

  3. Department of Cardiology, King's College London School of Medicine, James Black Centre, London, UK

    M Seddon & A M Shah

  4. Department of Women's and Children's Health, Paediatric Hepatobiliary Surgery, King's College Hospital, Denmark Hill, London, UK

    M Davenport

  5. Liver Transplantation and Hepatobiliary Surgery Service, Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK

    M Rela

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  1. J W Fabre
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  2. A Grehan
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  3. M Whitehorne
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  4. G J Sawyer
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  7. L Eckley
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  8. X Zhang
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  9. M Seddon
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  10. A M Shah
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  11. M Davenport
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Correspondence to J W Fabre.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Fabre, J., Grehan, A., Whitehorne, M. et al. Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava. Gene Ther 15, 452–462 (2008). https://doi.org/10.1038/sj.gt.3303079

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