September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Exploring the in vitro and in vivo anti-angiogenic effects of PI3K/Akt/mTOR drug combinations: A potential therapeutic option for Ocular Neovascularization
Author Affiliations & Notes
  • Temitope Sasore
    Department of Ocular Pharmacology and Genetics, University College Dublin, Dublin, Ireland
  • Breandan N Kennedy
    Department of Ocular Pharmacology and Genetics, University College Dublin, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Temitope Sasore, None; Breandan Kennedy, None
  • Footnotes
    Support  Irish Research Council. Marie Curie Industry-Academia Partnerships and Pathways (IAPP) FP7 IAPP grant 3D-NET, GA: 612218
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5027. doi:
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      Temitope Sasore, Breandan N Kennedy; Exploring the in vitro and in vivo anti-angiogenic effects of PI3K/Akt/mTOR drug combinations: A potential therapeutic option for Ocular Neovascularization. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5027.

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

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Abstract

Purpose : The pathophysiology of age-related macular degeneration (AMD), diabetic retinopathy (DR) and diabetic macula edema (DME) include inflammation, retinal angiogenesis and increased retinal vascular permeability (RVP). Although effective, current treatment regimens do not cause permanent regression of neo-vessels. Therefore, as the burden on society grows inexorably, drug combination approaches to treat these diseases are underway. Following on from our previous study documenting the additive or synergistic anti-angiogenic activity in vivo (Sasore and Kennedy 2014), we assess the biochemical impacts, safety and anti-angiogenic efficacy of these combinations in human endothelial cells and mouse model.

Methods : Immunoblots using phospho-specific antibodies assessed activation of PAM pathway signalling in human microvascular endothelial cells. The secretion of angiogenic factors was assessed in human retinal pigment epithelial (ARPE19) cells using multiplex and standard ELISA. Histological analysis of wildtype mouse (C57BL/6J) retina is used to assess the in vivo safety of PI3K/Akt/mTOR drug combinations. In addition, in vivo anti-angiogenic efficacy is examined in a mouse model of ocular developmental angiogenesis.

Results : Our results reveal that the most active PI3K/Akt/mTOR drug combinations additively inhibit phosphorylation of p70S6K protein and capillary tubule formation in human microvascular endothelial cell by ~20% compared to individual drugs alone. In addition, we report the additive/synergistic effects of these drug combinations on the secretion of angiogenic factors in ARPE19 cells. The drug combination LY294002 (5 mg/kg) and NVP-BEZ235 (5 mg/kg) are well tolerated and reduce developmental angiogenesis in mice by up to 20%.

Conclusions : In summary, combinations of PI3K/Akt/mTOR pathway inhibitors from zebrafish screens have been validated in human cell lines and mouse model of ocular angiogenesis. These drug combinations are additive or synergistic inhibitors of angiogenesis in vitro or in vivo. Further studies will evaluate the effect of these drugs on additional hallmarks of ocular neovascularization (ONV), including inflammation and permeability. In conclusion, PI3K/Akt/mTOR pathway drug combinations are potential therapeutic alternatives for treatment of ONV.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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