Longterm recombinant adeno-associated, virus-mediated, liver-generated expression of an angiogenesis inhibitor improves survival in mice with disseminated neuroblastoma

Journal of the American College of Surgeons
Christian J StreckAndrew M Davidoff

Abstract

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. The purpose of this study was to attempt to restrict the growth of disseminated neuroblastoma through delivery of a truncated, soluble form of the vascular endothelial growth factor receptor-2 (VEGFR-2 fetal liver kinase [Flk]-1), a decoy receptor for VEGF. Mice underwent portal vein injection of vector, either AAV-CAGG-tsFlk-1 or control vector. Subsequent truncated soluble fetal liver kinase-1 (tsFlk-1) expression was confirmed and quantified by ELISA. After 8 weeks, mice were given human neuroblastoma cells through the tail vein to establish disseminated disease and were sacrificed after 40 days. The weight of liver metastasis was measured. Intrahepatic tumor microvessel density and levels of apoptosis were determined. Survival was assessed in a second cohort of mice. After intraportal injection of AAV-CAGG-tsFlk-1, high-level, stable transgene expression was generated. Sera from these mice inhibited endothelial cell activation in vitro and Matrigel plug (BD Biosciences) neovascularization in vivo, suggesting that a systemic state of ...Continue Reading

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Citations

Apr 28, 2009·Advanced Drug Delivery Reviews·Zhihong Dong, Jacques E Nör
Jul 21, 2005·Technology in Cancer Research & Treatment·Paxton V DicksonAndrew M Davidoff
Sep 30, 2004·Technology in Cancer Research & Treatment·Kenneth Lundstrom
Apr 14, 2006·Human Genetics·Kenneth H Warrington, Roland W Herzog
Aug 8, 2006·Nature Medicine·Patricia S Steeg
Jan 13, 2016·World Journal of Gastroenterology : WJG·Yi-Gang WangYan-Fang Sun

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