March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Eye Drops Of Small Molecular Weight Inhibitor SRPIN340, Target SRPK1/2 To Control VEGF Mediated Choroidal Neovascularisation
Author Affiliations & Notes
  • Melissa V. Gammons
    Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
  • Masatoshi Hagiwara
    Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • Andrew D. Dick
    Ophthalmology, Univ of Bristol-Bristol Eye Hosp, Bristol, United Kingdom
  • David O. Bates
    Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom
  • Footnotes
    Commercial Relationships  Melissa V. Gammons, None; Masatoshi Hagiwara, None; Andrew D. Dick, None; David O. Bates, None
  • Footnotes
    Support  Fight for Sight, SCaRF
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2241. doi:
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      Melissa V. Gammons, Masatoshi Hagiwara, Andrew D. Dick, David O. Bates; Eye Drops Of Small Molecular Weight Inhibitor SRPIN340, Target SRPK1/2 To Control VEGF Mediated Choroidal Neovascularisation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2241.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose:
 

Choroidal neovascularization (CNV) is the primary cause of vision loss in patients with exudative age-related macular degeneration (AMD). Current anti-VEGF-A therapies have proven both safe and effective in randomized clinical trials, however, such treatments rely on intraocular injections as often as every month. VEGF is alternatively spliced to produce pro-angiogenic and anti-angiogenic families of sister isoforms. During pro-angiogenic isoform selection, SRSF1 (ASF/SF2) is phosphorylated by SRPK1, allowing its nuclear localization where it can bind to the proximal splice site (PSS) on VEGF pre-mRNA. Small molecule inhibitors of SRPK1 have been shown to switch VEGF splicing, such molecules are membrane permeable and show low toxicity. We therefore tested the hypothesis that topical application of a small molecule inhibitor of SRPK1/2, SRPIN340, could attenuate VEGF mediated CNV through selectively down-regulating pro-angiogenic isoform production.

 
Methods:
 

SRPIN340, an inhibitor of SRPK1 and SRPK2, was tested in a model of laser-induced choroidal neovascularisation in C57B/6 mice. Subsequent to laser photocoagulation 12 mice were treated with eye drops (20 drops over 14 days) containing SRPIN340 (100µg/ml, 10µg/ml, 1µg/ml, 0.1µg/ml) or vehicle in the control eye. The extent of CNV was analysed by flatmount of lectin stained choroids on day 14.

 
Results:
 

SRPIN340 eye drops dose dependently inhibited choroidal neovascularisation in treated eyes with an EC50 of 3.2µg/ml. SRPIN340 also altered the pro-angiogenic to anti-angiogenic VEGF balance in human primary retinal pigmented epithelial (RPE) cells from VEGF165 to VEGF165b at the RNA and protein level. Furthermore SRPIN340 reversed IGF-1 induced nuclear localization of SRSF1.

 
Conclusions:
 

SRPIN340, when given as eye drops, supressed VEGF mediated choroidal neovascularization. Furthermore, in addition to maintaining the production of cytoprotective VEGFxxxb isoforms, SRPIN340 treatment was not toxic to cells even at concentrations as high as 5mg/ml. This treatment could be an alternative therapy to anti-VEGF-A intraocular injections in patients with exudative AMD.  

 
Keywords: choroid: neovascularization • vascular endothelial growth factor • age-related macular degeneration 
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