Liver-targeted hydrodynamic gene therapy: Recent advances in the technique

Abstract

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

“…Furthermore, non-clinical studies for liver gene delivery have benefitted from the use of hydrodynamic (tail vein) injection to mice, a highly efficient delivery strategy, which requires the injection of a relatively high volume of liquid carrying the gene therapy vector. This high volume (up to 10% of body weight in rodents) causes a congestion in the right ventricle allowing retrograde flow of the gene therapy liquid back through the portal vein [52] at significant pressure. It is this transient increase in hepatic pressure that ensures efficient vector delivery throughout the organ.…”

Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach

“…Metabolic and genetic diseases, which show lower level of normal functional protein, are so far good candidates for this type of procedure. Although there is evidence showing transgene expression and that the procedure was safely performed in pigs [54][55][56][57], dogs [58,59], and baboons [60,61], further preclinical studies are necessary prior to human therapy application.…”

“…For its application in human, safety and efficacy of this approach have been extensively studied and improved. To date, various types of nucleic acid have been delivered by this approach in rodents as well as pigs [54][55][56][57], dogs [58,59], and rhesus monkeys [60,61]. Functional analyses of therapeutic gene were reported in nonalcoholic steatohepatitis [62], hepatitis B and C [63], fulminant hepatitis [64,65], liver fibrosis [66,67], liver regeneration [68], Fabry's disease [64], and colon cancer [69].…”

“…To achieve precise control of intravascular pressure, a computer-controlled injector with feedback mechanism has been developed [54]. Although the initial version of the injector utilized CO 2 as its driving force, the current version adopts electric motor for pursuit of more accurate control [58,77] ( Figure 5). This injection system leads to reproducible results of efficiency.…”

In Vivo Transgene Expression in the Pancreas by the Intraductal Injection of Naked Plasmid DNA

“…However, our knowledge regarding in vivo gene delivery targeting the pancreas and islets is currently very limited [3][4][5][6] , although many studies regarding in vivo gene delivery targeting other tissues including liver have been reported [7][8][9][10] . Even though this is a serious situation, Rehman et al reported that the adeno associated virus (AAV) 8-mediated gene transfer of interleukin-4 to pancreatic β cells prevents the onset of diabetes in non-obese diabetic mice 5 .…”