June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Development of SRPK1 inhibitors as novel anti-angiogenic therapeutics for exudative age-related macular degeneration (AMD)
Author Affiliations & Notes
  • Jennifer Batson
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Hamish Troop
    Chemistry, University of New South Wales, Sydney, NSW, Australia
  • Jonathan Rowlinson
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Claire Allen
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Roya Babaei-Jadidi
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Jingxue Zhang
    Chemistry, University of New South Wales, Sydney, NSW, Australia
  • Stephen Wearmouth
    Chemistry, University of New South Wales, Sydney, NSW, Australia
  • Stefan Knapp
    University of Oxford, Oxford, United Kingdom
  • Jonathan Morris
    Chemistry, University of New South Wales, Sydney, NSW, Australia
  • David Bates
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Footnotes
    Commercial Relationships Jennifer Batson, Exonate (F); Hamish Troop, None; Jonathan Rowlinson, Exonate (F); Claire Allen, Exonate (F); Roya Babaei-Jadidi, None; Jingxue Zhang, None; Stephen Wearmouth, None; Stefan Knapp, None; Jonathan Morris, Exonate (P); David Bates, Exonate (F), Exonate (I), Exonate (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2461. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Jennifer Batson, Hamish Troop, Jonathan Rowlinson, Claire Allen, Roya Babaei-Jadidi, Jingxue Zhang, Stephen Wearmouth, Stefan Knapp, Jonathan Morris, David Bates; Development of SRPK1 inhibitors as novel anti-angiogenic therapeutics for exudative age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2461.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Anti-angiogenic VEGF inhibitors are currently the standard of care for exudative AMD but must be administered monthly by intraocular injection and non-specifically inhibit all VEGF isoforms. Pathological angiogenesis occurs when the balance between pro-angiogenic VEGF-A165a and anti-angiogenic VEGF-A165b is switched by SRPK1-mediated differential splicing of VEGF mRNA to the proangiogenic form. We previously developed a small molecule inhibitor of SRPK1, termed SPHINX, that could inhibit SRPK1 at µM levels and were effective as eye drops in laser induced choroidal neovascularisation{Gammons, 2013 #4989}. We hypothesised that highly potent prelinical lead candidate SRPK1 inhibitors could be generated that can be given as topical eye drops and specifically inhibit pro-angiogenic VEGF-driven angiogenesis underlying wet AMD

Methods: Novel compounds were synthesized based on the structure of SPHINX. These were tested in in vitro kinase assays, thermal shift binding assays and in immunoprecipitation, immunoblotting and immunofluorescent cell based assays. Toxicity was evaluated by testing in vitro hERG activity, off-target gene splicing by RT-PCR and retinal toxicity by Ganzfeld ERG. Efficacy was tested using in vivo laser-induced CNV assay. Pharmacokinetics and bioavailability were evaluated in vivo and in an ex vivo permeability assay using mass spectrometry

Results: Novel compounds selectively bind to SRPK1 and dose-dependently inhibit SRPK1 kinase activity with IC50s <10 nM, SRSF1 phosphorylation and nuclear localization and VEGF-A165a protein levels. We identified compounds that do not inhibit hERG activity, splicing of off target genes or retinal function in vivo, yet potently inhibit laser-induced CNV following topical eye drop administration with EC50s of <500nM (n=6-8, P<0.05, One-way ANOVA). Compounds could be detected in the sclera/choroid and retina following eye drop administration in vivo and in ex vivo permeability assays

Conclusions: We have developed novel SRPK1 inhibitors that specifically target proangiogenic VEGF and can be delivered to the retina following topical eye drop administration to inhibit choroidal neovascularization. These compounds potentially offer for more specific, efficacious and safer therapeutics for patients with exudative AMD

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×