title: Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1.
abstract: The soluble vascular endothelial growth factor (VEGF) receptor 1 (sFLT1) has been tested in both animals and humans for anti-angiogenic therapies, for example, age-related macular degeneration. We hypothesized that adeno-associated viral vector (AAV)-mediated sFLT1 expression could be used to inhibit abnormal brain angiogenesis. We tested the anti-angiogenic effect of sFLT1 and the feasibility of using AAV serotype 9 to deliver sFLT1 through intravenous injection (IV) to the brain angiogenic region. AAVs were packaged in AAV serotypes 1 and 2 (stereotactic injection) and 9 (IV injection). Brain angiogenesis was induced in adult mice through stereotactic injection of AAV1-VEGF. AAV2-sFLT02 containing sFLT1 VEGF-binding domain (domain 2) was injected into the brain angiogenic region, and AAV9-sFLT1 was injected into the jugular vein at the time of or 4 weeks after AAV1-VEGF injection. We showed that AAV2-sFLT02 inhibited brain angiogenesis at both time points. IV injection of AAV9-sFLT1 inhibited angiogenesis only when the vector was injected 4 weeks after angiogenic induction. Neither lymphocyte infiltration nor neuron loss was observed in AAV9-sFLT1-treated mice. Our data show that systemically delivered AAV9-sFLT1 inhibits angiogenesis in the mouse brain, which could be utilized to treat brain angiogenic diseases such as brain arteriovenous malformation.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.|Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: F
authors.initials: F
authors.lastname: Shen
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mao
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Lawton
authors.affiliation: Sanofi-Genzyme R&D Center, Framingham, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pechan
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Colosi
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Sanofi-Genzyme R&D Center, Framingham, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Scaria
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Su
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011897:Random Allocation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1