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PURPOSE: Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. We tested the hypothesis that topical (eye drop) SRPK1-selective inhibitors could be generated that reduce pro-angiogenic isoforms, and prevent choroidal neovascularization in vivo. METHODS: Novel inhibitors were tested for SRPK inhibition in vitro, pro-angiogenic VEGF production in RPE cells by PCR and ELISA, and for inhibition of choroidal neovascularisation in mice and rats. RESULTS: A novel disubstituted furan inhibitor was selective for the SRPK family of kinases and reduced expression of pro-angiogenic but not antiangiogenic VEGF isoforms. This inhibitor and previously identified SRPK inhibitors significantly reduced choroidal neovascularisation in vivo. Topical administration of SRPK inhibitors dose-dependently blocked CNV with an EC50 of 9 μM. CONCLUSIONS: These results indicate that novel SRPK1 selective inhibitors could be a potentially novel topical (eye drop) therapeutic for wet AMD.

Original publication

DOI

10.1167/iovs.13-12422

Type

Journal article

Journal

Invest Ophthalmol Vis Sci

Publication Date

05/09/2013

Volume

54

Pages

6052 - 6062

Keywords

AMD, VEGF, splicing, Animals, Cells, Cultured, Choroidal Neovascularization, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Humans, Macular Degeneration, Mice, Mice, Inbred C57BL, Ophthalmic Solutions, Polymerase Chain Reaction, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, RNA, RNA Splicing, Rats, Retinal Pigment Epithelium, Vascular Endothelial Growth Factor A