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Gisela Velez, Hetian Lei, Andrius Kazlauskas, Shalesh Kaushal, Michael Young; SU9518 Inhibits Proliferative Vitreoretinopathy (PVR) in a Muller Cell Rabbit Model of PVR. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2065.
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© ARVO (1962-2015); The Authors (2016-present)
Platelet derived growth factor receptor alpha (PDGFRα) has been shown to play an important role in the development of PVR in both humans, and animal models of the disease. Disabling the PDGFRα has been shown to inhibit development of fibrous proliferation and contraction. SU9518 is a tyrosine kinase inhibitor which targets PDGFRα among other growth factor receptors. Previously we have shown that SU9518 can successfully inhibit PVR in a rabbit model using rabbit conjunctival fibroblasts (RCFs). We developed a model of PVR using retinal Muller cells modified to increase their expression of PDGFRα. We then test whether tyrosine kinase inhibitors such as SU9518 can inhibit PVR in this model.
The pLHDCX2 - PDGFRα retrovirus was used to stably express the PDGFRα in an immortalized human Muller cell line (MIO-M1). Western blot was used to confirm increased expression of PDGFRα in modified MIO-M1 cells (MIO-M1α). Forty-three rabbits underwent gas vitrectomy to their right eye with 0.1 ml of C3F8, followed one week later by intravitreal injection of 200K rabbit conjunctival fibroblasts (RCFs), MIO-M1, or MIO-M1α in 0.1 ml of DMEM and 0.1ml of platelet rich plasma (PRP). Twenty-one of these rabbits were injected with 300 µg of SU9518 in 0.1ml of BSS at the time of gas injection, controls were injected with BSS only. Eyes were examined by indirect ophthalmoscopy at days 2, 4, 7 and weekly thereafter for a total of 4 weeks after cell injection. Extent of PVR was graded using the Fastenberg classification.
Comparison of MIO-M1, MIO-M1α, and RCFs showed a dramatic increase in the pathogenecity of the MIO-M1α comparable to that of RCF’s, with a statistically significant difference in PVR induction when compared with MIO-M1 cells at day 7, 14, and 28. At day 28, 7/11 eyes injected MIO-M1α and only 1/11 eyes injected with MIO-M1 had developed severe (stage 3 or higher) PVR. In experimental eyes treated with SU9518, PVR was successfully inhibited in rabbit eyes injected with MIO-M1α, with only 1/11 eyes reaching stage 3 PVR or higher. Eyes injected with SU9518 and MIO-M1 had results comparable to fellow controls. None of the experimental eyes showed signs of retinal toxicity.
SU9518 is an effective inhibitor of PVR in our new rabbit model, and could potentially be used in humans for the treatment of PVR and other proliferative diseases involving fibrosis and gliosis. Further animal studies need to be performed to examine sustained delivery mechanisms.
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