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Melissa V. Gammons, Masatoshi Hagiwara, Andrew D. Dick, Dave O. Bates; SRPK1/2 Inhibition, By SRPIN340, As A Novel Therapeutic To Control VEGF Mediated Choroidal Neovascularisation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5928.
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Targeting vascular endothelial growth factor (VEGF), a critical stimulator of both retinal and choroidal neovascularisation, has proven an effective method of treatment in ocular degenerative diseases such as age-related macular degeneration (AMD). VEGF is alternatively spliced producing two families, pro-angiogenic VEGFxxx during proximal splice site (PSS) selection and anti-angiogenic VEGFxxxb when the distal splice site (DSS) is selected. VEGF splice site selection, determined by the binding of splicing factors, is thought to act through separate pathways for PSS and DSS selection. We wished to determine, as serine rich protein kinase 1 (SRPK1) causes the phosphorylation and nuclear localisation of the splicing factor, alternative splicing factor/splicing factor 2 (ASF/SF2), a promoter of PSS selection and pro-angiogenic isoform production, whether inhibiting splicing attenuated choroidal neovascularisation.
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 mice received two intraocular injections of 10, 6, 2, 1 or 0.2ng SRPIN340 in the ipsilateral eye and saline in the contralateral eye.
SRPIN340 suppressed choroidal neovascularisation dose dependently in treated eyes with an EC50 of 0.32ng/µl. SRPIN340 also altered the pro-angiogenic to anti-angiogenic VEGF balance in primary retinal pigmented epithelial (RPE) cells switching isoform production from VEGF165 to VEGF165b at the RNA level.
SRPIN340 inhibition of SRPK1/2 appeared to modulate splicing of VEGF to promote anti-angiogenic isoforms. Targeting SRPK1/2 has the potential to prevent VEGF mediated choroidal neovascularisation whilst maintaining the production of cytoprotective VEGFxxxb isoforms.
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