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Experimental Therapeutics |
Departments of Surgery [A. M. D., W. W. S., C. Y. C. N., J. Z.] and Hematology/Oncology [A. M. D., E. F. V.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; Department of Surgery, University of Tennessee College of Medicine, Memphis, Tennessee 38105 [A. M. D., W. W. S.]; and Department of Haematology, University College London, London WC1E 6HX, United Kingdom [A. C. N.]
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 ß–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.
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