April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Topical Application of a G-quartet Aptamer Attenuates Choroidal Neovascularization in a Murine Model of Age-Related Macular Degeneration
Author Affiliations & Notes
  • Derek Leaderer
    Ophthalmology, Tufts University School of Medicine, Boston, MA
  • Siobhan M Cashman
    Ophthalmology, Tufts University School of Medicine, Boston, MA
  • Rajendra Kumar-Singh
    Ophthalmology, Tufts University School of Medicine, Boston, MA
  • Footnotes
    Commercial Relationships Derek Leaderer, None; Siobhan Cashman, None; Rajendra Kumar-Singh, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 4948. doi:
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      Derek Leaderer, Siobhan M Cashman, Rajendra Kumar-Singh; Topical Application of a G-quartet Aptamer Attenuates Choroidal Neovascularization in a Murine Model of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4948.

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

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Abstract

Purpose: A G-quartet aptamer that binds to nucleolin (GAptN) has been previously shown to inhibit proliferation and induce cell cycle arrest. Elevated levels of nucleolin have been reported on endothelial cells during angiogenesis, a hallmark of the wet form of age-related macular degeneration (AMD). Currently, FDA-approved treatments for wet AMD are administered every 4 to 12 weeks via intravitreal injection, placing a large burden on patients and leading to significant side effects. In order to address the drawbacks of currently available therapies, we investigated the ability of topically applied GAptN for the attenuation of choroidal neovascularization (CNV) in a murine model of wet AMD.

Methods: We examined the anti-angiogenic properties of GAptN in vitro using the HUVEC tube formation assay. Fluorophore labeled GAptN and DNA control were subsequently applied topically to mouse eyes and used to localize GAptN in vivo. Efficacy of the aptamer administered intravitreally or topically in preventing angiogenesis in an in vivo setting was determined using laser-induced CNV, a model of wet AMD.

Results: GAptN was found to significantly reduce several markers of angiogenesis in vitro in the HUVEC tube formation assay, specifically GAptN reduced master junctions by 31%; master segments by 24.3% and mesh formation by 27%. Intravitreal injection of the fluorophore labeled GAptN indicated it's localization to the retina. Intravitreal injection of GAptN attenuated laser-induced CNV in mice by 30.9% and 37.6% relative to PBS or DNA control respectively. Injection of GAptN directly following laser-induced CNV was also found to decrease the area of macrophage infiltration by 30.9% and 37.6% relative to PBS and DNA control respectively. Single topical application of fluorophore labeled aptamer four days post-lasering demonstrated its ability to reach the retina in 50% of treated eyes. Importantly, topical application of GAptN prior to and daily post lasering reduced laser induced CNV by 47.2% and 43.4% relative to saline and DNA control treated mice respectively.

Conclusions: GAptN inhibits angiogenesis in vitro and attenuates CNV when injected intravitreally or, more importantly, when applied topically in the laser-induced model of AMD. Taken together, these findings support further investigation of topically applied GAptN as a potential therapeutic for wet AMD.

Keywords: 412 age-related macular degeneration • 453 choroid: neovascularization  
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