Impact of hydrodynamic injection and phiC31 integrase on tumor latency in a mouse model of MYC-induced hepatocellular carcinoma.
BACKGROUND
Hydrodynamic injection is an effective method for DNA delivery in mouse liver and is being translated to larger animals for possible clinical use. Similarly, phiC31 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 phiC31 integrase expression in tissue culture, leading to questions about safety.


RESULTS
To study whether hydrodynamic delivery alone, or in conjunction with delivery of phiC31 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 phiC31 integrase and donor plasmid were supplied to the mouse liver, the median tumor latency was 153 days, similar to mice receiving no injection.


CONCLUSIONS
Our data suggest that phiC31 integrase does not facilitate tumor formation in this C-MYC transgenic mouse model. However, in groups lacking phiC31 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.
Woodard
Lauren E
LE
Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
Keravala
Annahita
A
Jung
W Edward
WE
Wapinski
Orly L
OL
Yang
Qiwei
Q
Felsher
Dean W
DW
Calos
Michele P
MP
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D017931:DNA Primers; D005260:Female; D016259:Genes, myc; D019426:Integrases / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D017931:DNA Primers; D019426:Integrases