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A. L. Racanelli-Layton, B. Tam, T. Olafson, C. Virata, C.-C. Mak, J. Cao, J. Hood, G. Noronha, J. Doukas, R. Soll; A Topically Delivered VEGF/JAK2 Kinase Inhibitor Reduces Oxygen-Induced Retinopathy in a Murine Model. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4045.
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While vascular endothelial cell growth factor (VEGF) is generally viewed as the main growth factor responsible for ocular angiogenesis, recently erythropoietin (EPO) has been implicated in the angiogenic process associated with diabetic retinopathy (DR) as well. This study addresses whether a small molecule inhibitor of both VEGF and EPO signaling pathways reduces retinal neovascularization (NV) in a relevant animal model.
A novel chemical series was screened using enzymatic assays for kinase inhibitory activity against VEGF receptors (VEGFR) and Janus kinase 2 (JAK2), a signaling element downstream of EPO. A murine oxygen-induced retinopathy (OIR) model was then used to assess any in vivo influence on retinal NV. C57BL/6 mice were exposed to hyperoxia (75% oxygen) for 5 days starting on postnatal day 7 (P7), then returned to room air (21% oxygen) on P12. Test agents were delivered twice a day, by topical administration, for 5 days starting at P12. On P17, retinal flat mounts were stained with a lectin that binds murine endothelium (BSL I) and neovascular area quantified using image analysis software. Likewise, retinas were processed for real-time RT-PCR in order to follow VEGF and EPO mRNA levels.
TG101034 was selected based on its ability to inhibit both VEGFR and JAK2 (IC50= 22 and 8 nM, respectively). In the OIR model, this compound reduced retinal NV by 29% (p<0.05, n= 11-15) relative to the vehicle control group. RT-PCR confirmed roles for both VEGF and EPO in this model: while hyperoxia led to a 2-fold decrease in VEGF message, this then increased by 4-fold shortly upon return to normoxia before gradually falling. EPO message did not change upon hyperoxia but did spike 3-fold upon return to normoxia.
Oxygen cycling of mouse pups upregulates at least two important angiogenic factors, VEGF and EPO, and the topical administration of a dual JAK2/VEGFR inhibitor reduces the subsequent retinal NV that occurs in this model. With further development such kinase inhibitors may represent potential treatments for DR.
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