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

Abstract

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: Melissa V Gammons, Oleg Fedorov, David Ivison, Chunyun Du, Tamsyn Clark, Claire Hopkins, Masatoshi Hagiwara, Andrew D Dick, Russell Cox, Steven J Harper, Jules C Hancox, Stefan Knapp, David O Bates
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 54 Issue 9 Pg. 6052-62 (Sep 05 2013) ISSN: 1552-5783 [Electronic] United States
• PMID: 23887803 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ophthalmic Solutions
• Protein Kinase Inhibitors
• Vascular Endothelial Growth Factor A
• RNA
• Srpk1 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cells, Cultured
• Choroidal Neovascularization (drug therapy, genetics, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Humans
• Macular Degeneration (complications, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Ophthalmic Solutions (administration & dosage)
• Polymerase Chain Reaction
• Protein Kinase Inhibitors (administration & dosage)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• RNA (genetics)
• RNA Splicing
• Rats
• Retinal Pigment Epithelium (drug effects, metabolism, pathology)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)