April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Development of a Rabbit Model to Assess Anti-Angiogenic Therapies that Modulate Human VEGF-Mediated Retinal Vessel Pathology
Author Affiliations & Notes
  • Chad E. Bigelow
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Stephen Poor
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Yubin Qiu
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Shawn M. Hanks
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Michael Maker
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Elizabeth Fassbender
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Siyuan Shen
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Amber Woolfenden
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Bruce D. Jaffee
    Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts
  • Footnotes
    Commercial Relationships  Chad E. Bigelow, Novartis Institutes for Biomedical Research (E); Stephen Poor, Novartis Institutes for Biomedical Research (E); Yubin Qiu, Novartis Institutes for Biomedical Research (E); Shawn M. Hanks, Novartis Institutes for Biomedical Research (E); Michael Maker, Novartis Institutes for Biomedical Research (E); Elizabeth Fassbender, Novartis Institutes for Biomedical Research (E); Siyuan Shen, Novartis Institutes for Biomedical Research (E); Amber Woolfenden, Novartis Institutes for Biomedical Research (E); Bruce D. Jaffee, Novartis Institutes for Biomedical Research (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1384. doi:https://doi.org/
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      Chad E. Bigelow, Stephen Poor, Yubin Qiu, Shawn M. Hanks, Michael Maker, Elizabeth Fassbender, Siyuan Shen, Amber Woolfenden, Bruce D. Jaffee; Development of a Rabbit Model to Assess Anti-Angiogenic Therapies that Modulate Human VEGF-Mediated Retinal Vessel Pathology. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1384. doi: https://doi.org/.

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

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Abstract

Purpose: : To develop a large eye, non-primate model of VEGF-induced pathology for assessing anti-VEGF therapies.

Methods: : A range of intravitreally delivered VEGF doses (200-500 ng/eye human VEGF165) were given to Dutch Belted rabbits to select the optimal dose. Effects of repeated VEGF doses were assessed with periodic injections for up to 12 weeks. Inhibition of retinal vessel pathology was quantified 4 days after administration of ranibizumab (500 ug/eye) vs. vehicle control.Two complementary, noninvasive imaging methods were developed to assess retinal vessel pathology. One quantified changes in vessel diameter by scanning laser ophthalmoscope (SLO) images of vessels with i.v. FITC-labeled dextran in conjunction with optical coherence tomography (OCT). A complementary technique quantified vessel leakage 3 min. after i.v. fluorescein injection. Subtraction of the normalized and aligned FITC-dextran and fluorescein leakage images yielded the contribution of extravasated dye.

Results: : Retinal vessels responded to intravitreally injected VEGF consistently and repeatedly at an optimal dose of 400 ng. Lower doses induced milder pathology, while higher doses did not extend the range of measurable abnormalities. 48 hours post-VEGF injection, significant fluorescein leakage occurred concomitant with a 2-fold increase in vessel diameter by both FITC-dextran SLO images and OCT. Both abnormalities reverted to near normal 14 days after injection and were repeatedly induced for at least 5 cycles over 12 weeks. Ranibizumab completely inhibited both fluorescein leakage and vascular dilation.

Conclusions: : The retinal vasculature in the rabbit responds reproducibly to human VEGF165 in a manner that can be quantified with two complementary imaging modalities. This model offers a number of advantages. First, the model relies on human VEGF, so it can be used to study compounds without requiring non-human primates. Second, the ability to repeatedly test rabbits greatly reduces the number of animals required. Finally, the relatively large rabbit eye is amenable to testing clinical delivery devices.

Keywords: vascular endothelial growth factor • imaging/image analysis: non-clinical • neovascularization 
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