Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 54, Issue 9, Pages 6052-6062Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.13-12422
Keywords
VEGF; splicing; AMD
Categories
Funding
- Fight for Sight
- Skin Cancer Research Fund
- Richard Bright VEGF Research
- British Heart Foundation [PG11/20/28792]
- MRC [G10002073, MR/K020366/1, MR/K013157/1]
- BBSRC [BB/J007293/1]
- Japanese Society for the Promotion of Science
- Canadian Institutes for Health Research [1097737]
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- AbbVie
- Boehringer Ingelheim
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust [092809/Z/10/Z]
- Grants-in-Aid for Scientific Research [21249013] Funding Source: KAKEN
- BBSRC [BB/J007293/1] Funding Source: UKRI
- EPSRC [EP/I037229/1] Funding Source: UKRI
- MRC [MR/K020366/1, MR/K013157/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J007293/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/I037229/1] Funding Source: researchfish
- Heart Research UK [RG2594] Funding Source: researchfish
- Medical Research Council [MR/K020366/1, MR/K013157/1] Funding Source: researchfish
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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 mu M. CONCLUSIONS. These results indicate that novel SRPK1 selective inhibitors could be a potentially novel topical (eye drop) therapeutic for wet AMD.
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