July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
First-generation small molecule antagonists of profilin1 suppresses pathological retinal neovascularization
Author Affiliations & Notes
  • Xavier Guillonneau
    Institut de la Vision, INSERM, Paris, France
  • david martin gau
    Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • lucile vignaud
    Institut de la Vision, INSERM, Paris, France
  • Jordan Sturm
    Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Paul Francoeur
    Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • david koes
    Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Partha Roy
    Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Xavier Guillonneau, None; david gau, None; lucile vignaud, None; Jordan Sturm, None; Paul Francoeur, None; david koes, None; Partha Roy, None
  • Footnotes
    Support  NIH grant CA 108607
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2787. doi:
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      Xavier Guillonneau, david martin gau, lucile vignaud, Jordan Sturm, Paul Francoeur, david koes, Partha Roy; First-generation small molecule antagonists of profilin1 suppresses pathological retinal neovascularization. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2787.

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

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Abstract

Purpose : Angiogenesis, a process of new blood vessel generation, is a cause of visual impairment in ischemic retinopathies. A drawback of the standard of care anti-angiogenic therapy targeting VEGF signaling is the development of therapeutic resistance in some patients. Another issue is that VEGF is also a survival factor for neuronal and normal vascular endothelial cells (EC)<!--[endif]---->. Therefore, there is a crucial need for identification of additional therapeutic avenues. We sought to identify small molecule antagonists of profilin1 (Pfn1), an actin-binding protein with well-established pro-angiogenic function, as novel classes of anti-angiogenic molecules with potential applications in ocular pathology.

Methods : Non-cytotoxic first generation inhibitors of Pfn1:actin interaction were identified by computationally guided virtual screen of small molecule database followed by pyrene-actin polymerization biochemical screen and confirmatory proximity-ligation assays in vascular EC. Cellular F-actin level was assessed by rhodamine-phalloidin staining of cells followed by quantification. Time-lapse imaging was performed to measure the average speed of random migration of cells. Cell proliferation was assessed by counting cells in 2D cell culture. Matrigel-induced cord formation and mouse aortic ring assays were performed for in vitro and ex vivo angiogenesis studies, respectively. For in vivo angiogenesis, mouse pups were subjected to Oxygen-induced retinopathy (OIR): 7-days-old (P7) were exposed to 75% oxygen for 5 days and returned to room air at P12. Intravitreal injections with inhibitor were done at P12 and P14. At P17, vascular tufts and ischemic area were evaluated on BS-1 lectin immunostained flat-mounted retina.

Results : Antagonist of profilin1 (Pfn1) inhibited EC proliferation, migration and elicited potent anti-angiogenic activity in vitro and ex vivo. In OIR model, Pfn1 expression was found to be upregulated in mouse retinas. Finally, intravitreal administration of small molecule antagonist of pfn1:actin interaction caused a prominent reduction in ischemia-induced pathological retinal neovascularization in mouse pups.

Conclusions : In summary, these proof-of-concept studies lay a conceptual foundation for Pfn1-targeting next-generation anti-angiogenic agents for future development of new lines of therapies for certain retinal diseases that involve aberrant neovascularization.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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