July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
A novel approach to inhibit pro-angiogenic VEGF splicing in retinal vascular diseases with topical administration of small molecules optimised for retinal pharmacokinetics
Author Affiliations & Notes
  • Jennifer Batson
    Exonate Ltd, Cambridge, United Kingdom
  • Hamish Toop
    Exonate Ltd, Cambridge, United Kingdom
    University of New South Wales, Sydney, New South Wales, Australia
  • Susan Liddell
    Exonate Ltd, Cambridge, United Kingdom
  • James Daubney
    Exonate Ltd, Cambridge, United Kingdom
  • Elizabeth Stewart
    Exonate Ltd, Cambridge, United Kingdom
  • Ken McKechnie
    Exonate Ltd, Cambridge, United Kingdom
  • Jonathan Morris
    Exonate Ltd, Cambridge, United Kingdom
    University of New South Wales, Sydney, New South Wales, Australia
  • David Bates
    Exonate Ltd, Cambridge, United Kingdom
    School of Medicine, University of Nottingham, Nottingham, United Kingdom
  • Footnotes
    Commercial Relationships   Jennifer Batson, Exonate (E), Exonate (P); Hamish Toop, Exonate (P); Susan Liddell, Exonate (E); James Daubney, Exonate (E); Elizabeth Stewart, Exonate (E); Ken McKechnie, Exonate (E); Jonathan Morris, Exonate (P); David Bates, Exonate (I), Exonate (P), Exonate (E)
  • Footnotes
    Support  Wellcome Trust Seeding Drug Discovery Award
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 220. doi:
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      Jennifer Batson, Hamish Toop, Susan Liddell, James Daubney, Elizabeth Stewart, Ken McKechnie, Jonathan Morris, David Bates; A novel approach to inhibit pro-angiogenic VEGF splicing in retinal vascular diseases with topical administration of small molecules optimised for retinal pharmacokinetics. Invest. Ophthalmol. Vis. Sci. 2018;59(9):220.

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

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Abstract

Purpose : Development of non-invasive therapies for wAMD and DME has been unsuccessful due to insufficient PK/PD profiles to deliver efficacious doses to the retina. Delivery of potent small molecules to the retina as eye drops would be a treatment paradigm shift but remains an unmet need due to incomplete understanding of drug properties required. We hypothesised that trans-scleral permeability modelling could identify physicochemical properties required for eye drop administration enabling optimisation of inhibitors of the VEGF-A splicing kinase SRPK1.

Methods : Freshly enucleated porcine eyes were dissected and full thickness eye tissue was clamped into a scaffold. Compound levels were analysed by mass spectrometry at 24 h. More than 100 compounds were designed from predictive modelling based on physicochemical properties and screened. Efficacy, toxicity and PK were evaluated in vivo in C57/Bl6 mice. For PK in a larger eye, unanaesthetised pigmented rabbits were administered a single eye drop for successive timepoints or dosing for 6 days, then culled 16 hours afte the last injection. Eyes were dissected into regional segments and compound levels analysed by mass spectrometry (Mann-Whitney and Spearman tests for correlation).

Results : We identified potent and selective SRPK1 inhibitors that reduced angiogenic VEGF levels, with improved permeability ex vivo (ranging to 4.25 x 10-6 cm/s compared to 0.35 x 10-6 cm/s for pazopanib). Multiple regression analysis generated predicted permeability values which correlated with ex vivo permeability and in vivo retinal PK. SRPK1 inhibitors were equally distributed across the retina and detected in the vitreous at 4 h at significantly higher concentrations than pazopanib and at lower concentrations in plasma. Lead compounds had prolonged exposure compatible with twice daily eye drop administration. SRPK1 inhibitors potently inhibited laser-CNV following eye drop administration in mice (EC50s<0.5 μM, n=6-8, P<0.05).

Conclusions : Ex vivo permeability screening enabled modelling and design of novel compounds with improved permeability and optimisation for in vivo retinal delivery. Increased potency and ocular permeability of the novel SRPK1 inhibitors show potential to reach therapeutic levels in the retina following eye drop administration and improve treatment for patients with wAMD and DME.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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