July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Contractility can be reversed: discovering compounds with therapeutic potential for patients with Proliferative Vitreoretinopathy
Author Affiliations & Notes
  • Timothy A Blenkinsop
    Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Marie Fernandes
    Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Lauren Schiff
    Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Bar A Nachmani
    Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Footnotes
    Commercial Relationships   Timothy Blenkinsop, None; Marie Fernandes, None; Lauren Schiff, None; Bar Nachmani, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5255. doi:
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      Timothy A Blenkinsop, Marie Fernandes, Lauren Schiff, Bar A Nachmani; Contractility can be reversed: discovering compounds with therapeutic potential for patients with Proliferative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5255.

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

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Abstract

Purpose : Proliferative Vitreoretinopathy (PVR) is a metaplasia in the eye with contractile properties that lead to retinal detachment and vision loss. Retinal Pigment Epithelial cells contribute to PVR membranes and are thought to contribute towards the most aggressive contractile cases. We previously demonstrated TGFβ1 and TNFα can induce cobblestone RPE to form contractile membranes in vitro. We then compared these conditions to patient dissected PVR membranes by RNA-seq and found many overlapping pathways. Using this analysis we tested predicted compounds that negatively regulate genes in those pathways asking whether they may affect contractility.

Methods : Primary adult human RPE were cultured from human donor globes from the Eye Bank For Sight Restoration, NY, NY, using previously published protocols. After demonstration of native physiology RPE were then trypsinized and replated in DMEM/F12 with 3% FBS and treated with either TGFβ1, TNFα or the combination of TGFβ1 and TNFα together for 5 days then assayed for markers associated with PVR by qPCR, immunohistochemistry and Western blotting. SB202190 and Nicotinamide were also tested in combination with TGFβ1 and TNFα and examined similarly.

Results : We tested compounds known to suppress or block p38 signaling based on literature and previously conducted sequencing data, including SB202190 and nicotinamide. Both SB202190 and nicotinamide successfully prevented RPE from producing contractile membranes when costimulated TGFβ1and TNFα. We then allowed TGFβ1 and TNFα to induce membrane contraction before giving a second costimulation of TGFβ1 and TNFα plus either SB202190, or Nicotinamide to determine whether they can reverse already contracted membranes. Remarkably, timelapse imaging clearly demonstrates both SB202190 and Nicotinamide not only stop, but reverse membrane contractions.

Conclusions : Our studies found the co-stimulation of TGFb1 and TNFα models the contractile phenotype in PVR. Considering the contractility of PVR membranes lead to retinal detachment and vision loss, compounds that reverse TGFβ1 and TNFα co-stimulation induced contractile membranes in RPE may have therapeutic benefit for patients with contractile periretinal membranes.

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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