Hydrodynamic gene delivery to the liver: theoretical and practical issues for clinical application

Hydrodynamic gene delivery to the liver has potential as a safe and effective approach for clinical liver gene therapy. However, the simplicity of the technique in rodents - an intravenous injection - belies the theoretical and practical complexity for clinical application. A key issue is that outflow obstruction of the DNA solution from the liver is a critical factor for raising intrahepatic vascular pressure, which in turn provides the force to swell the liver and effect gene delivery. For conventional hydrodynamic gene delivery via tail vein injection, this outflow obstruction is provided naturally by the vascular resistance of the gut, spleen and pancreas. For regional hydrodynamic gene delivery to the liver, outflow obstruction to create a closed system requires surgical intervention, making it unlikely that minimally invasive techniques will be possible in the clinic. Intrinsic factors, in particular compliance (elasticity) of the liver are likely to be crucial in determining the degree of swelling for a given level of intrahepatic vascular pressure. Liver compliance is likely to be the major reason for the low level of hydrodynamic gene delivery in the pig model, and will influence the effectiveness of the approach in man, both in general and in different disease states.