title: Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.
abstract: OBJECTIVE
  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 pro-angiogenic 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.
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom. Melissa.Gammons@bris.ac.uk
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Gammons
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: David
authors.initials: D
authors.lastname: Ivison
authors.forename: Chunyun
authors.initials: C
authors.lastname: Du
authors.forename: Tamsyn
authors.initials: T
authors.lastname: Clark
authors.forename: Claire
authors.initials: C
authors.lastname: Hopkins
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.forename: Russell
authors.initials: R
authors.lastname: Cox
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008268:Macular Degeneration / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009883:Ophthalmic Solutions / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D012326:RNA Splicing; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D009883:Ophthalmic Solutions; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; C490215:Srpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: AMD; VEGF; splicing