May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Minimal Effective Dosing of a Novel Recombinant Form of VEGF Soluble Receptor 1 (sFlt-1) Delivered via AAV Vector in Inhibiting Choroidal Neovascularization in a Murine Model
Author Affiliations & Notes
  • W. W. Hauswirth
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • R. Miller
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • J. Pang
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • V. Choido
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • A. Abraham
    Genzyme Corporation, Framingham, Mississippi
  • P. Pechan
    Genzyme Corporation, Framingham, Mississippi
  • H. Rubin
    Genzyme Corporation, Framingham, Mississippi
  • S. Wadsworth
    Genzyme Corporation, Framingham, Massachusetts
  • Q. Li
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • Footnotes
    Commercial Relationships  W.W. Hauswirth, AGTC, P; R. Miller, None; J. Pang, None; V. Choido, None; A. Abraham, Genzyme, E; P. Pechan, Genzyme Corporation, E; H. Rubin, Genzyme Corporation, E; S. Wadsworth, Genzyme Corporation, E; Q. Li, None.
  • Footnotes
    Support  NIH grants EY13729, EY11123, NS36302, EY08571, Macular Vision Research Foundation, Foundation Fighting Blindness, Juvenile Diabetes Research Foundation and Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1375. doi:https://doi.org/
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      W. W. Hauswirth, R. Miller, J. Pang, V. Choido, A. Abraham, P. Pechan, H. Rubin, S. Wadsworth, Q. Li; Minimal Effective Dosing of a Novel Recombinant Form of VEGF Soluble Receptor 1 (sFlt-1) Delivered via AAV Vector in Inhibiting Choroidal Neovascularization in a Murine Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1375. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Choroidal neovascularization (CNV) occurs in variety of chorioretinal diseases, including age-related macular degeneration (AMD) and is the major cause of severe visual loss in patients with AMD. VEGF is known to be a critical stimulus for CNV. In a previous study, we showed that AAV-mediated delivery of a novel genetically engineered soluble form of VEGF receptor 1 (sFLT01) effectively inhibited CNV in an experimental animal model. In this study, we further investigated the minimal effective dose of the vector as a function of either intravitreal or subretinal routes of vector delivery in the mouse laser induced CNV model.

Methods: : The cDNA for sFLT01 was packaged into an AAV serotype-2 vector and the vector serially diluted in saline ranging from full dose (~5X108 vg/eye) to 1000 fold dilution (~5X105 vg/eye). Each dilution was injected either intravitreously or subretinally into the right eyes of 10-15 adult C57BL/6 mice. 532nm laser photocoagulation was performed 4-6 weeks after injection to focally rupture Bruch’s membrane in both eyes (4-5 sites each eye). The development of CNV at each laser burn was evaluated 14 days later by fluorescein angiographic choroidal flat-mount image analysis, as well as by histology of transverse retinal sections. The expression of the sFlt01 in the retina was confirmed by immunocytochemistry.

Results: : sFLT01was primarily expressed in the retinal ganglion cells when the AAV2-CBA-sFLT01 vector was injected intravitreously, and in photoreceptors and RPE cells when injected subretinally. The minimum effective dose was approximately 4X107 vg/eye when the vector was injected intravitreously, and resulted in about 40% reduction of the CNV area per laser burn. In contrast, minimum effective dose for subretinal vector was more than ten fold lower (< 4X106 vg/eye) than for intravitreal vector.

Keywords: choroid: neovascularization • gene transfer/gene therapy • age-related macular degeneration 
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