Details
Original language | English |
---|---|
Pages (from-to) | 6052-6062 |
Number of pages | 11 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 54 |
Issue number | 9 |
Publication status | Published - 13 Sept 2013 |
Externally published | Yes |
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
- Medicine(all)
- Ophthalmology
- Neuroscience(all)
- Sensory Systems
- Neuroscience(all)
- Cellular and Molecular Neuroscience
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Investigative Ophthalmology and Visual Science, Vol. 54, No. 9, 13.09.2013, p. 6052-6062.
Research output: Contribution to journal › Article › Research › peer review
}
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.
KW - AMD
KW - Splicing
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=84883642880&partnerID=8YFLogxK
U2 - 10.1167/iovs.13-12422
DO - 10.1167/iovs.13-12422
M3 - Article
C2 - 23887803
AN - SCOPUS:84883642880
VL - 54
SP - 6052
EP - 6062
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 9
ER -