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

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • 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

Externe Organisationen

  • University of Bristol
  • University of Oxford
  • Kyoto University
  • University of Nottingham
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Seiten (von - bis)6052-6062
Seitenumfang11
FachzeitschriftInvestigative Ophthalmology and Visual Science
Jahrgang54
Ausgabenummer9
PublikationsstatusVeröffentlicht - 13 Sept. 2013
Extern publiziertJa

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.

ASJC Scopus Sachgebiete

Zitieren

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, Jahrgang 54, Nr. 9, 13.09.2013, S. 6052-6062.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-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, Jg. 54, Nr. 9, S. 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 Sep 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 ; Jahrgang 54, Nr. 9. S. 6052-6062.
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title = "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 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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TY - JOUR

T1 - Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD

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.

PY - 2013/9/13

Y1 - 2013/9/13

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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