Topical anti-angiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative-AMD

Melissa V Gammons, Oleg Federov, David Ivison, Chunyun Du, Tamsyn L Clark, Claire Hopkins, Masatoshi Hagiwara, Andrew D Dick, Russell J Cox, Steven J Harper, Jules C Hancox, Stefan Knapp, David O Bates

Research output: Contribution to journalArticle (Academic Journal)

33 Citations (Scopus)

Abstract

PURPOSE. Exudative age related macular degeneration (wet AMD) is treated by monthly injection into the eye of anti-vascular endothelial growth factor (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 anti-angiogenic VEGF isoforms. This inhibitor and previously identified SRPK inhibitors significantly reduced choroidal neovascularisation in vivo. Topical adminstration of SRPK inhibitors dose dependently blocked CNV with an EC50 of 9µM. CONCLUSIONS. These results indicate that novel SRPK1 selective inhibitors could be potential novel topical (eye drop) therapeutics for wet AMD.
Original languageEnglish
JournalInvestigative Ophthalmology and Visual Science
DOIs
Publication statusPublished - 25 Jul 2013

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