rAAV-mediated long-term liver-generated expression of an angiogenesis inhibitor can restrict renal tumor growth in mice.
It is now well established that tumor growth is angiogenesis dependent. Inhibition of angiogenesis, therefore, is likely to be an effective anticancer approach. A gene therapy-mediated approach to the delivery of antiangiogenic agents using adeno-associated virus (AAV) vectors has a number of advantages, including the potential for sustained expression. We have constructed a rAAV vector in which the expression of a soluble, truncated form of the vascular endothelial growth factor receptor-2 (Flk-1), a known inhibitor of endothelial cell activation, is driven by a composite beta-actin-based promoter. After intraportal injection of this vector, high-level, stable transgene expression was generated in mice. This established a systemic state of angiogenesis inhibition; sera from these mice inhibited endothelial cell activation in vitro and Matrigel plug neovascularization in vivo. Significant antitumor efficacy was observed in two murine models of pediatric kidney tumors. Tumor development was prevented in 10 of 15 (67%) mice, with significant growth restriction of tumors in the remaining mice. For the first time, long-term, in vivo expression of a functional angiogenesis inhibitor has been established using rAAV, with resultant anticancer efficacy in a relevant, orthotopic tumor model. These findings establish the feasibility of using rAAV vectors in antiangiogenic gene therapy.
Davidoff
Andrew M
AM
Department of Surgery, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. andrew.davidoff@stjude.org
Nathwani
Amit C
AC
Spurbeck
William W
WW
Ng
Catherine Y C
CY
Zhou
Junfang
J
Vanin
Elio F
EF
D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D009396:Wilms Tumor / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1