Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer.
A number of preclinical and human clinical gene therapy trials using adenoviral vectors have shown that the number of viral particles necessary to give adequate levels of gene transfer can be associated with significant vector-related toxicity. In an effort to reduce the number of adenoviral particles required for a given level of gene transfer, we sought to redirect adenoviral infection via a receptor that is highly expressed on the target cells. By using basic fibroblast growth factor (FGF2) as the targeting ligand, adenovirus-mediated gene transfer to the human ovarian cancer cell line SKOV3.ip1 was significantly enhanced, permitting the transduction of a greater number of target cells to be achieved by a given dose of virus. In a murine model of human ovarian carcinoma, an FGF2-redirected adenoviral vector carrying the gene for herpes simplex virus thymidine kinase (AdCMVHSV-TK) was shown to result in a significant prolongation of survival compared with the same number of particles of unmodified AdCMVHSV-TK. In addition, equivalent survival rates were achieved with a 10-fold lower dose of the FGF2-redirected AdCMVHSV-TK compared with the unmodified vector. To our knowledge, this is the first report demonstrating that strategies to enhance the efficiency of in vivo transduction of adenoviral vectors will be of clinical utility.
Rancourt
C
C
Gene Therapy Program, Comprehensive Cancer Center, University of Alabama at Birmingham, 35294, USA.
Rogers
B E
BE
Sosnowski
B A
BA
Wang
M
M
Piché
A
A
Pierce
G F
GF
Alvarez
R D
RD
Siegal
G P
GP
Douglas
J T
JT
Curiel
D T
DT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000401:mortality / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology*; D015996:Survival Rate; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D016222:Fibroblast Growth Factor 2; D013937:Thymidine Kinase