May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Externally Regulated AAV-Mediated Delivery of PEDF Ameliorates the OIR Phenotype
Author Affiliations & Notes
  • G. A. Silva
    F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania
  • D. C. Chung
    F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania
  • J. Bennicelli
    F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania
  • J. Bennett
    F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania
  • Footnotes
    Commercial Relationships  G.A. Silva, None; D.C. Chung, None; J. Bennicelli, None; J. Bennett, None.
  • Footnotes
    Support  FCT (Portugal) Fellowship SFRH/BPD/23440/2005. K08 EY017024. NIH Grant EY10820. Foundation Fighting Blindness. Research to Prevent Blindness. Paul&Evanina Mackall Foundation Trust. FM Kirby Foundation
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1127. doi:https://doi.org/
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    • Get Citation

      G. A. Silva, D. C. Chung, J. Bennicelli, J. Bennett; Externally Regulated AAV-Mediated Delivery of PEDF Ameliorates the OIR Phenotype. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1127. doi: https://doi.org/.

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

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Abstract

Purpose: : Our goal was to generate a system which allows efficient, rapid onset, and externally regulated retinal transgene expression through delivery mediated by AAV2/8. To demonstrate functionality of this system, we used a rapamycin-regulated two-plasmid system and AAV2/8 to deliver the cDNA encoding Pigment Epithelium-Derived Factor (PEDF) to the retina in the oxygen-induced retinopathy (OIR) model of retinal neovascularization.

Methods: : Two AAV2/8 viruses were generated: one carrying a CMV promoter driven activation domain and binding domain. The other contained the PEDF cDNA, 12 ZFHD1 binding sites, the IL-2 promoter, and an IRES-GFP sequence. The efficiency of the two-plasmid system was tested in vitro prior to generating the AAVs, using different concentrations of rapamycin. Postnatal (p)3 pups were injected intravitreally with the two AAV2/8s. Contralateral eyes received AAV2/8.eGPF. After exposure to 75% oxygen for 5 days starting at p7, pups were returned to room air and given 4mg/kg/day of rapamycin until assessment of neovascular response. Controls included non-injected and injected animals maintained in room air. Neovascular response was assessed by angiography and histopathology.

Results: : Expression of PEDF, detectable through co-expression of GFP was rapamycin-dependent. Eyes receiving AAV2/8.PEDF.IRES.GFP had decreased or no neovascular tufts, although the normal vasculature was not as robust compared to that in animals kept in room air. Neovascular tufts were apparent in control ROP mice but not in PEDF-treated animals.

Conclusions: : The results indicate that PEDF, delivered via AAV2/8 through an externally regulatable system, results in amelioration of neovascularization in the OIR model. Ongoing experiments aim to further characterize the transduction properties and ocular safety of this system.

Keywords: retinal neovascularization • gene transfer/gene therapy • growth factors/growth factor receptors 
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