Department of Hepatology and Transplantation, King's College London School of Medicine, London, SE5 9NU, United Kingdom.
Hum Gene Ther. 2011 Jul;22(7):879-87. doi: 10.1089/hum.2010.144. Epub 2011 Mar 7.
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.
肝内流体力学基因递送是临床肝基因治疗中很有前途的方法，但在较大物种中基因表达水平远低于啮齿动物。为加压各个肝段开发手术技术，以及确定肝血管解剖实际上是否允许加压各个肝段，是需要解决的关键问题。我们通过门静脉和肝静脉分支，在猪肝的各个肝段上应用流体力学基因递送的方法，评估了这些问题。我们的目的是开发外科技术，用小容量实现肝内各个肝段的高血管压力，但不中断门静脉血流或减少静脉回流到心脏。我们报告，如果没有特定的外科干预措施来阻止 DNA 溶液从目标肝段流出，肝内血管压力几乎没有或没有增加。我们首次证明，在不损害门静脉血流或静脉回流到心脏的情况下，可选择性加压各个肝段。因此，在临床环境中实现各个肝段的流体力学基因递送在技术上是可行的，但需要开腹手术，而不是微创技术。
