July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Idelalisib inhibits neovascularization in a mouse model of oxygen-induced retinopathy
Author Affiliations & Notes
  • wenyi wu
    Schepens Eye Research Institure, Boston, Massachusetts, United States
    opthalmology, xiangya hosipitol, Changsha, hunan, China
  • Guohong Zhou
    Schepens Eye Research Institure, Boston, Massachusetts, United States
  • Xionggao Huang
    Schepens Eye Research Institure, Boston, Massachusetts, United States
  • Patricia A D'Amore
    Schepens Eye Research Institure, Boston, Massachusetts, United States
  • Shizuo Mukai
    Schepens Eye Research Institure, Boston, Massachusetts, United States
  • Hetian Lei
    Schepens Eye Research Institure, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   wenyi wu, None; Guohong Zhou, None; Xionggao Huang, None; Patricia D'Amore, None; Shizuo Mukai, None; Hetian Lei, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5299. doi:
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      wenyi wu, Guohong Zhou, Xionggao Huang, Patricia A D'Amore, Shizuo Mukai, Hetian Lei; Idelalisib inhibits neovascularization in a mouse model of oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5299.

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

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Abstract

Purpose : Phosphoinositide 3-kinases (PI3Ks) play a critical role in transmitting signals from the cell surface to intracellular protein effectors. Deregulation of PI3Ks may initiate multiple diseases including pathological angiogenesis, which is associated with proliferative diabetic retinopathy and wet age-related macular degeneration. The goal of this project is to compare the efficacy of idelalisib, a specific inhibitor of PI3Kd, to that of anti-vascular endothelial grow factor (VEGF) agents (e.g. aflibercept and ranibizumab) in inhibiting VEGF-induced activation of Akt, cellular responses of primary human retinal microvascular endothelial cells (HRECs) and neovascurization in a mouse model of oxygen-induced retinopathy (OIR).

Methods : Expression of PI3K p110d in cell lines of rabbit conjuctival fibroblasts, 661W mouse cone cells, HRECs, human umbilical vascular endothelial cells, and human lymphatic endothelial cells was examined by western blot. HRECs were treated with idelalisib (1, 5, 10 and 20 mM) for 24 hours and cell survival was measured. The effect of idelalisib on VEGF-induced Akt phosphorylation (Ser 473) and cellular responses (e.g. proliferation, migration and tube formation) was compared to that of aflibercept or ranibizumab. Angiogenesis was induced in a mouse model of OIR and idelalisib (10 mM) was intravitreally injected on post-natal day (P12).On P17 the mouse retinas were stained with endothelial marker Isolectin B4 and neovascularization was quantified for statistic analysis.

Results : PI3K p110d was expressed in the examined vascular ECs, and its expression in HRECs was much higher than that in 661W cells. Within 24 hours idelalisib at 10 mM did not show toxicity to HRECs. Notably, idelalisib at its selective dose (5 mM) was superior to aflibercept or ranibizumab in inhibition of VEGF-induced activation of Akt. In addition, 5 mM idelalisib significantly prevented VEGF-induced proliferation, migration and tube formation of HRECs. Furthermore, this drug has more potential than aflibercept or ranibizumab in inhibiting VEGF-induced cellular responses. Moreover, idelalisib at 10mM inhibited neovascularization in a mouse model of OIR.

Conclusions : Idelalisib may serve as an alterative drug for therapeutic intervention of intraocular pathological angiogenesis.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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