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J. Hua, C. Spee, E. Baron, S. Kase, A. J. Churchill, S. J. Ryan, S. Harper, D. R. Hinton, D. O. Bates; Therapeutic Potential of Small Molecule Splicing Factor-inhibitor Srpin340 in Treatment of Choroidal Neovascularization (cnv). Invest. Ophthalmol. Vis. Sci. 2009;50(13):2333.
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Alternative splicing of the vascular endothelial growth factor A (VEGF-A) in 8th exon by choice of proximal splice side produces major angiogenic VEGF-A isoforms such as VEGF165, while distal splice side produces potent anti-angiogenic ones, such as VEGF165b. Inhibition of the splicing factor kinase SRPK1/2 via a small molecule SRPIN340 has previously been shown to block ASF/SF2 phosphorylation, while the inhibition of distal splice site selection is brought about by the Clk inhibitor TG003. We therefore compared TG003 and SRPIN340 in CNV.
Four CNV lesions were induced by diode laser in each eye of C57B/L6J mice. 2µl of 50µM SRPIN340 or TG003 (TG), or vehicle (PBS) was injected into the vitreous. Two weeks later, fluorescein angiography (FA) was carried out before animals sacrificed and eyes dissected for sclero-choroid whole mount or sectioned and stained with Isolectin B4 or H&E, and examined under confocal or light microscopy.
Intra-vitreous injection of SRPIN340 significantly reduced leakage of lesions in FA (1.9±0.5, PBS 2.4±0.3, TG 2.4±0.5, p<0.001 ANOVA, n=20), volume (2.6±0.9, PBS 5.7±2.9, TG 5.1±2.2 ×105 µm3 p<0.001, ANOVA, n=10), surface area (3.0±0.9, PBS 6.0±3.1, TG 5.0±2.5 ×105 µm2 p<0.001 ANOVA, n=10) and cross-sectional area (1.5±0.6, PBS 2.9±0.7, TG 2.3±1.2 ×105 µm2 p<0.001 ANOVA, n=10).
SRPIN340 significantly inhibited CNV in a mouse model and maybe a potential therapeutic candidate for ocular neovascular diseases in the future. Modulation of alternative splicing of VEGF-A 8th exon using small molecules is an effective novel treatment strategy for neovascular diseases.
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