Abstract
BackgroundHydrodynamic injection is an effective method for DNA delivery in mouse liver and is being translated to larger animals for possible clinical use. Similarly, ϕC31 integrase has proven effective in mediating long-term gene therapy in mice when delivered by hydrodynamic injection and is being considered for clinical gene therapy applications. However, chromosomal aberrations have been associated with ϕC31 integrase expression in tissue culture, leading to questions about safety.Methodology/Principal FindingsTo study whether hydrodynamic delivery alone, or in conjunction with delivery of ϕC31 integrase for long-term transgene expression, could facilitate tumor formation, we used a transgenic mouse model in which sustained induction of the human C-MYC oncogene in the liver was followed by hydrodynamic injection. Without injection, mice had a median tumor latency of 154 days. With hydrodynamic injection of saline alone, the median tumor latency was significantly reduced, to 105 days. The median tumor latency was similar, 106 days, when a luciferase donor plasmid and backbone plasmid without integrase were administered. In contrast, when active or inactive ϕC31 integrase and donor plasmid were supplied to the mouse liver, the median tumor latency was 153 days, similar to mice receiving no injection.Conclusions/SignificanceOur data suggest that ϕC31 integrase does not facilitate tumor formation in this C-MYC transgenic mouse model. However, in groups lacking ϕC31 integrase, hydrodynamic injection appeared to contribute to C-MYC-induced hepatocellular carcinoma in adult mice. Although it remains to be seen to what extent these findings may be extrapolated to catheter-mediated hydrodynamic delivery in larger species, they suggest that caution should be used during translation of hydrodynamic injection to clinical applications.
Highlights
Hydrodynamic injection of plasmid DNA involves a rapid, high-volume injection of DNA into the tail vein of mice [1,2]
Different groups were tracked to provide survival times that could be compared statistically to determine if the treatments had an effect on the length of time between induction of C-MYC expression in the liver and sacrifice due to tumor burden, a time frame defined in this study as ‘‘tumor latency.’’ We hypothesized that since QC31 integrase is associated with chromosomal aberrations in tissue culture, its expression might decrease tumor latency in these tumor-prone mice
Such mouse models are available for most organs that may be targeted by different gene therapy methods
Summary
Hydrodynamic injection of plasmid DNA involves a rapid, high-volume injection of DNA into the tail vein of mice [1,2]. This method can provide delivery of DNA to as many as 40% of hepatocytes and has been widely adopted for delivery of nucleic acids to mouse liver. Catheter-mediated adaptations of the method have been developed for DNA delivery in larger animals, opening the possibility of clinical use for gene therapy [3]. Hydrodynamic injection is an effective method for DNA delivery in mouse liver and is being translated to larger animals for possible clinical use. Chromosomal aberrations have been associated with QC31 integrase expression in tissue culture, leading to questions about safety
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