1] Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan [2] Department of Pharmaceutical Sciences, University of Pittsburgh, School of Pharmacy, Pittsburgh, Pennsylvania, USA.
Mol Ther Nucleic Acids. 2013 Oct 15;2(10):e128. doi: 10.1038/mtna.2013.52.
Development of a safe and effective method for gene delivery to hepatocytes is a critical step toward gene therapy for liver diseases. Here, we assessed the parameters for gene delivery to the livers of large animals (pigs, 40-65 kg) using an image-guided hydrodynamics-based procedure that involves image-guided catheter insertion into the lobular hepatic vein and hydrodynamic injection of reporter plasmids using a computer-controlled injector. We demonstrated that injection parameters (relative position of the catheter in the hepatic vasculature, intravascular pressure upon injection, and injection volume) are directly related to the safety and efficiency of the procedure. By optimizing these parameters, we explored for the first time, the advantage of the procedure for sequential injections to multiple lobes in human-sized pigs. The optimized procedure resulted in sustained expression of the human α-1 antitrypsin gene in livers for more than 2 months after gene delivery. In addition, repeated hydrodynamic gene delivery was safely conducted and no adverse events were seen in the entire period of the study. Our results support the clinical applicability of the image-guided hydrodynamic gene delivery method for the treatment of liver diseases.Molecular Therapy-Nucleic Acids (2013) 2, e128; doi:10.1038/mtna.2013.52; published online 15 October 2013.
开发一种安全有效的方法将基因递送至肝细胞是肝脏疾病基因治疗的关键步骤。在此，我们利用一种基于图像引导的流体动力学的程序，评估了向大型动物（猪，40-65kg）肝脏进行基因传递的参数，该程序包括使用计算机控制的注射器，通过图像引导的导管插入肝小叶静脉和在血管内注射报告质粒。我们证明，注射参数（导管在肝脉管系统中的相对位置、注射时的血管内压力和注射体积）与该程序的安全性和效率直接相关。通过优化这些参数，我们首次探索了该程序在人大小型猪中对多个叶进行序贯注射的优势。经优化的程序导致人α-1 抗胰蛋白酶基因在基因传递后 2 个月以上持续表达。此外，重复的流体动力基因传递是安全进行的，在整个研究期间未观察到不良反应。我们的结果支持图像引导的流体动力学基因传递方法用于治疗肝脏疾病的临床适用性。Molecular Therapy-Nucleic Acids (2013) 2, e128; doi:10.1038/mtna.2013.52; published online 15 October 2013.
