Abstract
The efficacy of noninvasive interventionist catheterism in large animals as an alternative to the hydrodynamic procedure, described for small animals, is evaluated. Basically, gene transfer is performed by implantation and fixation of a balloon catheter within the suprahepatic vein of anesthetized pigs, through the femoral vein. The catheter tip is identified by fluoroscopy, injecting a contrast solution that marks large or small hepatic territories. Animals were injected with a 100 ml pTG7101 plasmid solution (40 μg/ml), which contains the human alpha-1 antitrypsin gene, perfused at a rate of 7.5 ml/s and efficacy and toxicity of the procedure were evaluated. The results show: (i) the highest efficacy in protein production is reached when perfusion is limited to small areas of the liver; (ii) no relevant hepatic toxicity was observed; (iii) gene transfer is mainly located in the areas around the central vein, as seen in the immunohistochemical studies; (iv) the electron microscopy studies indicate that the areas with good transfection efficacy show the presence of abundant endocytic vesicles that may even fuse among themselves. These data suggest that retrovenous injection by noninvasive interventionist catheterism could become an efficient procedure for hepatic gene transfer with potential clinical applications.
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References
Davern TJ . Molecular therapeutics of liver disease. Liver Dis 2001; 52: 381–414.
Strauss M . Liver-directed gene therapy: prospects and problems. Gene Therapy 1994; 1: 156–164.
Herweijer H, Wolff JA . Progress and prospects: naked DNA gene transfer and therapy. Gene Therapy 2003; 10: 453–458.
Budker V, Zhang G, Knechtle S, Wolff JA . Naked DNA delivered intraportally expresses efficiently in hepatocytes. Gene Therapy 1996; 3: 593–598.
Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.
Zhang G, Song YK, Liu D . Long-term expression of human alpha1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using a hydrodynamics-based procedure. Gene Therapy 2000; 7: 1344–1349.
Liu F, Huang L . Improving plasmid DNA-mediated liver gene transfer by prolonging its retention in the hepatic vaculature. J Gene Med 2001; 3: 569–598.
Liu F, Huang L . Electric gene transfer to the liver following systemic administration of plasmid DNA. Gene Therapy 2001; 9: 1116–1119.
Aliño SF, Crespo A, Dasí F . Long-term therapeutic levels of human alpha-1-antitrypsin in plasma after hydrodynamic injection of nonviral DNA. Gene Therapy 2003; 10: 1672–1679.
Ferber D . Gene therapy: safer and virus-free? Science 2001; 294: 1638–1642.
Liu F, Lei J, Vollmer R, Huang L . Mechanism of liver gene transfer by mechanical massage. Mol Ther 2004; 9: 452–457.
Zhang G, Gao X, Song YK, Vollmer R, Stolz DB, Gasiorowki JZ et al. Hydroporation as the mechanism of hydrodynamic delivery. Gene Therapy 2004; 11: 675–682.
Crespo A, Peydro A, Dasi F, Benet M, Calvete JJ, Revert F et al. Hydrodynamic liver gene transfer mechanism involves transient sinusoidal blood stasis and massive endocytic vesicles. Gene Therapy 2005; 12: 927–935.
Eastman SJ, Baskin KM, Hodges BL, Chu Q, Gates A, Dreusicke R et al. Development of catheter-based procedures for transducing the isolated rabbit liver with plasmid DNA. Hum Gene Ther 2002; 13: 2065–2077.
Habib N . Hydrodynamic Gene Delivery. ASCO/International Society of Cancer Gene Therapy: Orlando, FL, USA, 2005.
Herrero MJ, Dasi F, Noguera I, Sanchez M, Moret I, Sanmartin I et al. Mouse and pig nonviral liver gene therapy: success and trials. 8th International Conference: Emerging Technologies in Drug and Gene-based Therapeutics. Crete. Gene Ther Mol Biol 2005; 9: 169–180.
Zhang G, Budker V, Wolf JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.
Dasí F, Benet M, Crespo J, Crespo A, Alino SF . Asialofetuin liposome-mediated human alpha 1-antitrypsin gene transfer in vivo results in stable long-term gene expression. J Mol Med 2001; 79: 205–212.
Acknowledgements
We thank Mr Alejo Sempere from the Department of Pathology, University of Valencia, for the performance of the immunohistochemistry and the SCSIE from University of Valencia for the electron microscopy facilities. This work has been partially supported by GV04B-179, GVACOMP06/217 and SAF2004-08161 projects from Generalidad Valenciana and Ministerio de Educación y Ciencia.
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Aliño, S., Herrero, M., Noguera, I. et al. Pig liver gene therapy by noninvasive interventionist catheterism. Gene Ther 14, 334–343 (2007). https://doi.org/10.1038/sj.gt.3302873
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DOI: https://doi.org/10.1038/sj.gt.3302873
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