Image-guided, Lobe-specific Hydrodynamic Gene Delivery to Swine Liver

Kamimura, Kenya; Suda, Takafumi; Xu, Wei; Zhang, Guisheng; Liu, Dexi

doi:10.1038/mt.2008.294

Cited by 92 publications

(125 citation statements)

References 17 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…To avoid this adverse effect, we have described a retrograde cathetermediated gene delivery procedure 5 with the aim of locally reproducing the intrahepatic conditions mediated by tail vein hydrodynamic injection. However, all the studies reported in pigs 4,5,[11][12][13][14] and in human clinical trials 3 indicate that the efficiency of the procedure remains several orders of magnitude lower than observed in mice. The exact reason for the low gene transfer efficiency of retrograde injection is still unknown, but the low resistance of the sinusoid bed must be a very important factor, as DNA can easily travel across the liver segment after hepatic vein injection, reaching the portal vein and then freely returning to the inferior cava vein through another liver segment.…”

Section: Discussionmentioning

confidence: 98%

DNA delivery to ‘ex vivo’ human liver segments

et al. 2011

View full text Add to dashboard Cite

Hydrodynamic injection is an efficient procedure for liver gene therapy in rodents but with limited efficacy in large animals, using an 'in vivo' adapted regional hydrodynamic gene delivery system. We study the ability of this procedure to mediate gene delivery in human liver segments obtained by surgical resection. Watertight liver segments were retrogradely injected from hepatic vein with a saline solution containing a plasmid bearing the enhanced green fluorescent protein (eGFP) gene, under different conditions of flow rate (1, 10 and 20 ml s -1 ) and final perfused volume. Samples were cultured for 1 to 2 days and used for microscopy and molecular analysis of gene expression. The fluorescent and immunohistochemistry studies indicated that in segments injected at X10 ml s -1 , good and wide gene expression was present in the liver sections and the molecular analysis reinforced the histological observation in a quantitative manner (index of apparent gene delivery: 10 2 -10 4 eGFP DNA copy per 100 pg of total DNA; transcription index: 10 5 -2Â10 6 eGFP RNA copy per 100 ng of total RNA). In addition, injected gold nanoparticles (15 nm diameter) suggested that DNA delivery to hepatocytes must involve a facilitated permeation process without membrane disruption. In summary, we show that retrograde venous injection of watertight human liver segment is an anadromous procedure that results in wide liver gene delivery and good gene expression. However, additional studies will be necessary to clarify the influence of the prolonged ischemia injury to hepatocytes in our model.

show abstract

Section: Discussionmentioning

confidence: 98%

DNA delivery to ‘ex vivo’ human liver segments

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In gene therapy studies, hydrodynamic delivery of plasmid DNA has generated gene product at the therapeutic level and resulted in complete cure of diseases (8)(9)(10)(11). By combining the technique of image-guided catheter insertion with a computer-controlled injection device (12), we have demonstrated successful gene delivery to cells in the liver (13) and skeletal muscle (14) in pigs, suggesting that site-specific gene delivery can be achieved in large animals and it is feasible to apply hydrodynamic gene delivery to treatment of human diseases.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Gene Transfer in Rats by Tail Vein Injection of Plasmid DNA

Zhou

Kamimura

Zhang

et al. 2010

AAPS J

Self Cite

View full text Add to dashboard Cite

Abstract. In this study, we examined the effect of various factors on gene delivery efficiency of tail vein injection of plasmid DNA into rats. We measured the level of reporter gene expression in the internal organs including the lung, heart, spleen, kidney, and liver as function of injection volume, injection time, and DNA dose. Persistency of reporter gene expression in transfected animals was also examined. We demonstrated that plasmid delivery to rats by the tail vein is effective as long as the volume of injected DNA solution is adjusted to 7-8% of body weight with an injection time of less than 10 s. With the exception of a short-term increase in serum concentration of alanine aminotransferase and transient irregularity in cardiac function during and soon after the injection, the procedure is well tolerated. Lac Z staining of the liver from transfected animals showed approximately 5-10% positive cells. Persistency test for transgene expression in animals using plasmid carrying cDNA of human alpha 1 antitrypsin gene driven by chicken beta actin gene promoter with CMV enhancers showed peak level of transgene product 1 day after the injection followed by a gradual decline with time. Peak level was regained by a second injection performed on day 38 after the first injection. These results show that tail vein injection is an effective means for introducing plasmid DNA into liver cells in rats. We believe that this procedure will be extremely useful for gene function studies in the context of whole animal in rats.

show abstract

“…The technique involves the rapid injection of large volumes of DNA solution into a peripheral (usually the tail) vein, using volumes amounting to B10% of the body weight in mice (B2.5 ml) 1,2 and B8-10% of body weight in rats (B20-25 ml). 3,4 However, although there have been six published reports in the pig [5][6][7][8][9][10] and one clinical trial, 11 none of these has provided levels of gene delivery remotely close to those seen in mice and rats. In the pig studies, levels of reporter gene expression were o1% of those in concurrent studies in rodents, while there was no substantive evidence for gene expression in the clinical study.…”

Section: Introductionmentioning

confidence: 99%

Technical requirements for effective regional hydrodynamic gene delivery to the left lateral lobe of the rat liver

2010

View full text Add to dashboard Cite

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 o1% 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 (B1.5 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.

show abstract

Image-guided, Lobe-specific Hydrodynamic Gene Delivery to Swine Liver

Cited by 92 publications

References 17 publications

DNA delivery to ‘ex vivo’ human liver segments

DNA delivery to ‘ex vivo’ human liver segments

Intracellular Gene Transfer in Rats by Tail Vein Injection of Plasmid DNA

Technical requirements for effective regional hydrodynamic gene delivery to the left lateral lobe of the rat liver

Contact Info

Product

Resources

About