Catheter-mediated Intravascular Delivery to Liver

Non-viral gene delivery offers a number of advantages over viral gene delivery with regard to safety and potential deleterious immune effects. Until recently however, efficient gene delivery to liver in vivo was only possible using viral vectors. Now, working closely with University of Wisconsin scientists, Mirus Bio Corporation has developed an intravascular delivery method that allows for the efficient delivery of genes to liver cells using non-viral vectors. Using this technology, high level gene expression in hepatocytes can be achieved via delivery to the bile duct, portal vein, or inferior vena cava/hepatic vein. Recent experiments have shown that it is now possible to achieve microgram/ml amounts of secreted protein (alkaline phosphatase) in the bloodstream of a primate.

Collaborators at Genzyme have investigated procedures for minimally invasive hydrodynamic gene delivery [ref: Eastman et al.]. In one technique, they isolated hepatic lobes using a balloon occlusion balloon catheter to occlude selected hepatic veins. In a second technique, a whole organ was targeted wherein the entire hepatic venous system was isolated and the pDNA solution injected hydrodynamically into the vena cava between two balloons used to block hepatic venous outflow. Significant levels of reporter gene expression and secretion were achieved, suggesting that with further refinement hydrodynamic delivery of pDNA to an isolated liver may be a useful method for human gene therapy.

Potential Therapeutic Applications:

• Liver cancer
• Metabolic Diseases

Benefits of the Technology:

• Up to 10% of hepatocytes can be transfected from a single injection in small and large animal models including non-human primates.
• A variety of liver vessels can be used including portal vein, hepatic vein or artery and bile duct.
• Able to target entire liver or specific liver lobes.
• Able to regulate level of gene delivery by adjusting delivery conditions.
• Amenable to delivery of naked DNA or DNA:polymer complexes.
• Able to obtain microgram/ml amounts of secreted protein in the bloodstream of primates.

References:

X. Zhang, X. Dong, G. Sawyer, L. Collins, John Fabre. Regional Hydrodynamic Gene Delivery to the Rat Liver with Physiological Volumes of DNA Solution. J Gene Med 6:693-703, 2004

S. Eastman, K Baskin, B. Hodges, Q. Chu, A. Gates, R. Dreusicke, S. Anderson, R. Scheule. Development of Catheter-Based Procedures for Transducing the Isolated Rabbit Liver with Plasmid DNA. Hum Gen Ther 13:2065-2077, 2002

G. Zhang, V. Budker, P. Williams, V. Subbotin and J.A. Wolff. Efficient expression of naked DNA delivered intraarterially to limb muscles of nonhuman primates. Hum Gen Ther 12:427-438, 2001.

H. Herweijer, Zhang G. Subbotin VM. Budker V. Williams P. Wolff JA. Time course of gene expression after plasmid DNA gene transfer to the liver. Journal of Gene Medicine. 3(3):280-91, 2001 May-Jun.

V. Budker, Budker T. Zhang G. Subbotin V. Loomis A. Wolff JA. Hypothesis: naked plasmid DNA is taken up by cells in vivo by a receptor-mediated process. Review. Journal of Gene Medicine. 2(2):76-88, 2000 Mar-Apr.

G. Zhang, V. Budker and J. A. Wolff. High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 10:1735-7, 1999.

V. Budker, G. Zhang, I. Danko, P. Williams and J. A. Wolff. The efficient expression of intravascularly delivered DNA in rat muscle. Gene Ther 5:272-6, 1998.

G. Zhang, D. Vargo, V. Budker, N. Armstrong, S. Knechtle and J. A. Wolff. Expression of naked plasmid DNA injected into the afferent and efferent vessels of rodent and dog livers. Hum Gene Ther 8:1763-72, 1997.

V. Budker, G. Zhang, S. Knechtle and J. A. Wolff. Naked DNA delivered intraportally expresses efficiently in hepatocytes. Gene Ther 3:593-8, 1996.