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Jinggang Yin, Weihong Huo, Kip Guy, Edward Chaum; Inhibition of Experimental PVR by a Novel Nutlin-3 Analogue. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5322.
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Proliferative vitreoretinopathy (PVR) is a common complication of open globe injury and the most common cause of failed retinal detachment surgery. The response by RPE cells liberated into the vitreous includes proliferation, migration, and epithelial mesenchymal transition (EMT) and plays a central role in the development and progression of PVR. We developed a new rabbit PVR model, in which TGF-beta activated human ARPE19 cells were stimulated to undergo EMT and form tractional membranes in vivo. Novel Nutin-3 analogues were tested in vitro and in vivo to determine potential clinical efficacy using the model.
PVR was induced in the right eye of Dutch-belted rabbits by injection of TGF-beta-activated ARPE19 cells 1 week following gas vitrectomy as has been previously reported. The ARPE19 cells were treated with 10ng/ml TGF-b2 for 48 hours, harvested, washed, and injected at a concentration of 30,000cells/100ul. Nutlin-3 analogues, synthesized at St. Jude Children’s Research Hospital, were screened for inhibition of RPE cell proliferation in vitro. Analogue SJ-211 was the most effective drug used topically in treated group and is reported here. All rabbits were examined weekly by indirect ophthalmoscopy and selected retinas were photographed. PVR was graded using the standard Fastenberg classification from 0 to 5. The progression of disease grade levels was quantified using Fisher exact statistics.
The cell proliferation analysis indicated that ARPE19 cell proliferation were significantly inhibited in 72 hours at 1.0 µm levels using several analogues including SJ- 0211, SJ-0212 and SJ-055. SJ-0211 showed the strongest inhibitory effects and was used for in vivo studies.Topically daily use SJ-0211 reduced the trajectories of disease progression in treated rabbits, in particular disease progression seen after 3 weeks, and was significantly different from the control group for up to six weeks (p< 0.01). Intravitreal drug concentrations were verified in the rabbit vitreous in parallel with the presented studies.
Our studies show that topical treatment using Nutlin-3 analogue SJ-0211 inhibits EMT-activated human RPE cell proliferation in vitro and in the rabbit model of PVR. It represent a new group of drugs that may have therapeutic potential to inhibit the development and progression of PVR via topical delivery.
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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