Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.
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...
| Hauptverfasser: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Sprache: | English |
| Veröffentlicht: |
2013
|
| _version_ | 1826279013999443968 |
|---|---|
| author | Gammons, M Fedorov, O Ivison, D Du, C Clark, T Hopkins, C Hagiwara, M Dick, A Cox, R Harper, S Hancox, J Knapp, S Bates, DO |
| author_facet | Gammons, M Fedorov, O Ivison, D Du, C Clark, T Hopkins, C Hagiwara, M Dick, A Cox, R Harper, S Hancox, J Knapp, S Bates, DO |
| author_sort | Gammons, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:52:31Z |
| format | Journal article |
| id | oxford-uuid:7316a35a-ae4b-4580-b702-447a1f74e0ee |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:52:31Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:7316a35a-ae4b-4580-b702-447a1f74e0ee2022-03-26T19:54:14ZTopical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7316a35a-ae4b-4580-b702-447a1f74e0eeEnglishSymplectic Elements at Oxford2013Gammons, MFedorov, OIvison, DDu, CClark, THopkins, CHagiwara, MDick, ACox, RHarper, SHancox, JKnapp, SBates, DOPURPOSE: 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. |
| spellingShingle | Gammons, M Fedorov, O Ivison, D Du, C Clark, T Hopkins, C Hagiwara, M Dick, A Cox, R Harper, S Hancox, J Knapp, S Bates, DO Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title | Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title_full | Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title_fullStr | Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title_full_unstemmed | Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title_short | Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. |
| title_sort | topical antiangiogenic srpk1 inhibitors reduce choroidal neovascularization in rodent models of exudative amd |
| work_keys_str_mv | AT gammonsm topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT fedorovo topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT ivisond topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT duc topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT clarkt topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT hopkinsc topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT hagiwaram topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT dicka topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT coxr topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT harpers topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT hancoxj topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT knapps topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd AT batesdo topicalantiangiogenicsrpk1inhibitorsreducechoroidalneovascularizationinrodentmodelsofexudativeamd |