Rapamycin-regulated control of antiangiogenic tumor therapy following rAAV-mediated gene transfer.
Regulated gene expression may be required for the clinical development of certain gene therapies. Several approaches have been developed that allow pharmacologic control of transgene expression, including the dimerizer-regulated transcriptional system in which rapamycin or its analogs function as transcriptional inducers. These compounds can also act as direct antitumor agents via inhibition of mammalian target of rapamycin (mTOR). We describe the development of an optimized recombinant adeno-associated virus (AAV) expression cassette that allows dimerizer-regulated gene expression from a single vector in vitro and in vivo. After demonstrating multiple cycles of rapamycin-dependent transgene induction following a single administration of an AAV vector in vivo, application of this regulated AAV gene expression system to the pharmacologic control of antiangiogenic therapy was evaluated in preclinical tumor models. Dimerizer-regulated vectors were constructed encoding a soluble inhibitor of the vascular endothelial growth factor (VEGF) pathway. In two subcutaneous models of glioblastoma, regulated expression of the VEGF inhibitor via recombinant AAV-mediated gene transfer, in combination with rapamycin, was shown to decrease tumor growth rate significantly. The dual properties of rapamycin--as a transcriptional inducer and mTOR inhibitor--are exploited in combination with an AAV-encoded antiangiogenic agent to provide a novel approach for the treatment of malignant diseases.
Nguyen
Minh
M
Cell Genesys Inc., South San Francisco, California, USA. minhn@cellgenesys.com
Huan-Tu
Guang
G
Gonzalez-Edick
Melissa
M
Rivera
Victor M
VM
Clackson
Tim
T
Jooss
Karin U
KU
Harding
Thomas C
TC
D043168:Angiostatins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D011228:Prealbumin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
D007166:Immunosuppressive Agents; D011228:Prealbumin; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus