title: Critical physiological and surgical considerations for hydrodynamic pressurization of individual segments of the pig liver.
abstract: Hydrodynamic gene delivery to the liver is a promising approach for liver gene therapy in the clinic, but levels of gene expression in larger species have been much less than in rodents. The development of surgical techniques for pressurizing individual liver segments and the establishment of whether hepatic vascular anatomy in fact permits pressurization of individual segments are critical issues that need to be addressed. We have evaluated these issues using hydrodynamic delivery to individual segments of the pig liver, via branches of both portal and hepatic veins. Our objective was to develop surgical techniques that achieve elevated vascular pressures within individual liver segments with small volumes, but without interruption of portal blood flow or reduction in venous return to the heart. We report that, without specific surgical interventions to obstruct outflow of DNA solution from the targeted liver segment, little or no increase in intrahepatic vascular pressure occurs. We demonstrate, for the first time, that selective pressurization of individual liver segments is possible without compromising portal venous flow or venous return to the heart. Thus, hydrodynamic gene delivery to individual liver segments is technically achievable in a clinical setting, but will require open abdominal surgery rather than minimally invasive techniques.
authors.affiliation: Department of Hepatology and Transplantation, King's College London School of Medicine, London, SE5 9NU, United Kingdom. john.fabre@kcl.ac.uk
authors.forename: John W
authors.initials: JW
authors.lastname: Fabre
authors.forename: Michael
authors.initials: M
authors.lastname: Whitehorne
authors.forename: Aidan
authors.initials: A
authors.lastname: Grehan
authors.forename: Greta J
authors.initials: GJ
authors.lastname: Sawyer
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Davenport
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rela
mesh_terms: D000818:Animals; D001794:Blood Pressure; D004247:DNA / Q000008:administration & dosage; D005260:Female; D005471:Fluoroscopy; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D057446:Hydrodynamics; D008099:Liver / Q000502:physiology* / Q000601:surgery*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism; D013552:Swine
chemical_list: D004247:DNA; D008156:Luciferases