May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Prevention and Reversal of Drusen-Like Phenotype in a Mouse Model of Amd
M. E. Kleinman; B. J. Raisler; A. Takeda; R. J. C. Albuquerque; M. Nozaki; J. Baffi; W. W. Hauswirth; J. Ambati
Author Affiliations & Notes
  • M. E. Kleinman
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • B. J. Raisler
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • A. Takeda
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • R. J. C. Albuquerque
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • M. Nozaki
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • J. Baffi
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • W. W. Hauswirth
    Molecular Genetics and Ophthalmology, University of Florida, Gainesville, Florida
  • J. Ambati
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky
  • Footnotes
    Commercial Relationships M.E. Kleinman, None; B.J. Raisler, None; A. Takeda, None; R.J.C. Albuquerque, None; M. Nozaki, None; J. Baffi, None; W.W. Hauswirth, None; J. Ambati, None.
  • Footnotes
    Support NIH Grant EY015422-03
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2354. doi:
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      M. E. Kleinman, B. J. Raisler, A. Takeda, R. J. C. Albuquerque, M. Nozaki, J. Baffi, W. W. Hauswirth, J. Ambati; Prevention and Reversal of Drusen-Like Phenotype in a Mouse Model of Amd. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2354.

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Abstract

Purpose:: Mice deficient in the monocyte chemoattractant protein Ccl2 or its receptor Ccr2 develop drusen-like basal laminar deposits as they age. We employed targeted gene therapy coupled with bone-marrow transplantation (BMT) to prevent or reverse the early AMD-like phenotype in young and aged mice, respectively.

Methods:: Adeno-associated virus (AAV) vectors encoding Ccl2 or green fluorescent protein (GFP) were injected subretinally into fellow eyes of 8-9 month-old Ccl2-/- mice with drusen-like spots (n=9) or 4-8 week-old Ccl2-/- mice without drusen-like spots (n=9). BMT from wild-type mice constitutively expressing LacZ was performed in a group of AAV treated Ccl2-/- x Ccr2-/- mice (n=6). Fundus photography, electron microscopy, and immunohistochemical analyses were conducted on treated eyes at 14, 28, and 72 days following viral injections. F4/80+ CD11c- macrophage infiltration into the retina or choroid at 72 days was quantified by flow cytometry.

Results:: AAV-mediated expression of Ccl2 prevented and reversed the drusen-like phenotype in Ccl2 deficientmice. Fundus and ultrastructural examinations showed decreased sub-RPE basal laminar deposits and hard drusen-like excrescences in eyes injected with AAV-Ccl2 compared with AAV-GFP. BMT treated animals exhibited similar findings. Immunohistochemistry demonstrated persistent expression of Ccl2 in AAV-Ccl2 injected eyes and the presence of LacZ+ bone-marrow derived cells in the eyes of BMT animals. Significantly more macrophages were mobilized in the AAV-Ccl2 treated eyes compared to AAV-GFP with a predilection for migration to the choroid.

Conclusions:: These rescue data confirm a critical role of the Ccl2-Ccr2 signaling axis in the prevention and regression of drusen-like basal laminar deposits. Gene therapy and BMT were able to upregulate Ccl2 expression and demonstrate that the drusen-like phenotype is both preventable and reversible by restoration of macrophage mobilization.

Keywords: age-related macular degeneration • immunomodulation/immunoregulation • gene transfer/gene therapy 
© 2007, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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