Abstract
Hydrodynamic gene delivery to the liver is an attractive approach for clinical liver gene therapy, but critical aspects of technique remain uncertain. There has not been to date any report of high levels of hydrodynamic gene delivery to the liver, except in rodents. Regional hydrodynamic delivery to individual lobes/segments of the liver is being pursued in preclinical pig models, where reporter gene expression has been <1% of rodent levels, and in one clinical study, where there was no substantive evidence of gene expression. In none of these studies did surgical technique include outflow obstruction of the DNA solution. Here we report a novel technique for regional hydrodynamic gene delivery to the left lateral lobe of the rat liver. The technique gives high levels of gene delivery specific to the left lateral lobe with low volumes (∼1.5 ml) of DNA solution, and permits an evaluation of hydrodynamic delivery in the presence and in the absence of outflow obstruction. We report that outflow obstruction is an absolute requirement for effective hydrodynamic gene delivery to individual lobes/segments of the liver, and therefore that minimally invasive techniques will not be possible in the clinic.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.
Liu F, Song Y, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.
Maruyama H, Higuchi N, Nishikawa Y, Kameda S, Iino N, Kazama JJ et al. High-level expression of naked DNA delivered to rat liver via tail vein injection. J Gene Med 2002; 4: 333–341.
Sawyer GJ, Dong X, Whitehorne M, Grehan A, Seddon M, Shah AM et al. Cardiovascular function following acute volume overload for hydrodynamic gene delivery to the liver. Gene Therapy 2007; 14: 1208–1217.
Herrero MJ, Dasi F, Noguera I, Sanchez M, Moret I, Sanmartin I et al. Mouse and pig non-viral liver gene therapy: success and trials. Gene Ther Mol Biol 2005; 9: 169–180.
Yoshino H, Hashizume K, Kobayashi E . Naked plasmid DNA transfer to the porcine liver using rapid injection with large volume. Gene Therapy 2006; 13: 1696–1702.
Aliño SF, Herrero MJ, Noguera I, Dasí F, Sánchez M . Pig liver gene therapy by noninvasive interventionist catheterism. Gene Therapy 2007; 14: 334–343.
Suda T, Suda K, Liu D . Computer-assisted hydrodynamic gene delivery. Mol Ther 2008; 16: 1098–1104.
Fabre JW, Grehan A, Whitehorne M, Sawyer GJ, Dong X, Salehi S et al. Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava. Gene Therapy 2008; 15: 452–462.
Kamimura K, Suda T, Xu W, Zhang G, Liu D . Image-guided, lobe-specific hydrodynamic gene delivery to swine liver. Mol Ther 2009; 17: 491–499.
Khorsandi SE, Bachellier P, Weber JC, Greget M, Jaeck D, Zacharoulis D et al. Minimally invasive and selective hydrodynamic gene therapy of liver segments in the pig and human. Cancer Gene Ther 2008; 15: 225–230.
Zhang G, Gao X, Song YK, Vollmer R, Stolz DB, Gasiorowski JZ et al. Hydroporation as the mechanism of hydrodynamic delivery. Gene Therapy 2004; 11: 675–682.
Sawyer GJ, Rela M, Davenport M, Whitehorne M, Zhang X, Fabre JW . Hydrodynamic gene delivery to the liver: theoretical and practical issues for clinical application. Curr Gene Ther 2009; 9: 128–135.
Zhang X, Dong X, Sawyer GJ, Collins L, Fabre JW . Regional hydrodynamic gene delivery to the rat liver with physiological volumes of DNA solution. J Gene Med 2004; 6: 693–703.
Sawyer GJ, Grehan A, Dong X, Whitehorne M, Seddon M, Shah AM et al. Low volume hydrodynamic gene delivery to the rat liver via an isolated segment of the inferior vena cava: efficiency, cardiovascular response and intrahepatic vascular dynamics. J Gene Med 2008; 10: 540–550.
Wisse E, Jacobs F, Topal B, Frederik P, De Geest B . The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Therapy 2008; 15: 1193–1199.
Miyatsuka T, Kaneto H, Kajimoto Y, Hirota S, Arakawa Y, Fujitani Y et al. Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis. Biochem Biophys Res Comm 2003; 310: 1017–1025.
Acknowledgements
We acknowledge the support from the Rosetrees Trust.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Gene Therapy website
Supplementary information
Supplementary Information 1
Technique for hydrodynamic gene delivery to the left lateral lobe of the liver in the rat. (MPG 264663 kb)
Supplementary Information 2
Hydrodynamic gene delivery WITHOUT outflow obstruction. (MPG 10646 kb)
Rights and permissions
About this article
Cite this article
Sawyer, G., Zhang, X. & Fabre, J. Technical requirements for effective regional hydrodynamic gene delivery to the left lateral lobe of the rat liver. Gene Ther 17, 560–564 (2010). https://doi.org/10.1038/gt.2009.167
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2009.167
Keywords
This article is cited by
-
Human AAT gene transfer to pig liver improved by using a perfusion isolated organ endovascular procedure
European Radiology (2016)
-
Hemodynamics of a hydrodynamic injection
Molecular Therapy - Methods & Clinical Development (2014)
-
DNA delivery to ‘ex vivo’ human liver segments
Gene Therapy (2012)