Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.

Journal article

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.

Authors: Gammons, M; Fedorov, O; Ivison, D; Du, C; Clark, T

• Publication status: Published
• Journal: Investigative ophthalmology and visual science
• Volume: 54
• Issue: 9
• Pages: 6052-6062
• Publication date: 2013-09-01
• DOI: 10.1167/iovs.13-12422
• EISSN: 1552-5783
• ISSN: 0146-0404
• Language: English
• Keywords: Choroidal Neovascularization; Rats; RNA Splicing; Enzyme-Linked Immunosorbent Assay; RNA; Protein-Serine-Threonine Kinases; Retinal Pigment Epithelium; Macular Degeneration; Mice, Inbred C57BL; Protein Kinase Inhibitors; Ophthalmic Solutions; Vascular Endothelial Growth Factor A; Mice; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Polymerase Chain Reaction; Cells, Cultured; Animals