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

Research output: Contribution to journalArticleResearchpeer review

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

External Research Organisations

  • University of Bristol
  • University of Oxford
  • Kyoto University
  • University of Nottingham
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Details

Original languageEnglish
Pages (from-to)6052-6062
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume54
Issue number9
Publication statusPublished - 13 Sept 2013
Externally publishedYes

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 proangiogenic 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.

Keywords

    AMD, Splicing, VEGF

ASJC Scopus subject areas

Cite this

Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. / Gammons, Melissa V.; Fedorov, Oleg; Ivison, David et al.
In: Investigative Ophthalmology and Visual Science, Vol. 54, No. 9, 13.09.2013, p. 6052-6062.

Research output: Contribution to journalArticleResearchpeer review

Gammons, MV, Fedorov, O, Ivison, D, Du, C, Clark, T, Hopkins, C, Hagiwara, M, Dick, AD, Cox, R, Harper, SJ, Hancox, JC, Knapp, S & Bates, DO 2013, 'Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD', Investigative Ophthalmology and Visual Science, vol. 54, no. 9, pp. 6052-6062. https://doi.org/10.1167/iovs.13-12422
Gammons, M. V., Fedorov, O., Ivison, D., Du, C., Clark, T., Hopkins, C., Hagiwara, M., Dick, A. D., Cox, R., Harper, S. J., Hancox, J. C., Knapp, S., & Bates, D. O. (2013). Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Investigative Ophthalmology and Visual Science, 54(9), 6052-6062. https://doi.org/10.1167/iovs.13-12422
Gammons MV, Fedorov O, Ivison D, Du C, Clark T, Hopkins C et al. Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Investigative Ophthalmology and Visual Science. 2013 Sept 13;54(9):6052-6062. doi: 10.1167/iovs.13-12422
Gammons, Melissa V. ; Fedorov, Oleg ; Ivison, David et al. / Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. In: Investigative Ophthalmology and Visual Science. 2013 ; Vol. 54, No. 9. pp. 6052-6062.
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AU - Gammons, Melissa V.

AU - Fedorov, Oleg

AU - Ivison, David

AU - Du, Chunyun

AU - Clark, Tamsyn

AU - Hopkins, Claire

AU - Hagiwara, Masatoshi

AU - Dick, Andrew D.

AU - Cox, Russell

AU - Harper, Steven J.

AU - Hancox, Jules C.

AU - Knapp, Stefan

AU - Bates, David O.

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N2 - 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 proangiogenic 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.

AB - 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 proangiogenic 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.

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