June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Visual behaviour-based screening of a randomised chemical library identifies small molecules that restore vision.
Author Affiliations & Notes
  • Breandan N Kennedy
    UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    UCD Conway Institute, University College Dublin, Dublin, Ireland
  • John Fehilly
    UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Marc Cerrada-Gimenez
    R&D Division, Experimentica Ltd, Kuopio, Finland
  • Simon Kaja
    Departments of Ophthalmology and Molecular Pharmacology & Neuroscience, Loyola University Chicago, Chicago, Illinois, United States
    R&D Division, Experimentica Ltd, Kuopio, Finland
  • Giedrius Kalesnykas
    R&D Division, Experimentica Ltd, Kuopio, Finland
  • Robert Scoffin
    Cresset BioMolecular Discovery Ltd, Litlington, Cambridgeshire, United Kingdom
  • Justine O'Brien
    UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    UCD Conway Institute, University College Dublin, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Breandan Kennedy None; John Fehilly None; Marc Cerrada-Gimenez Experimentica, Code E (Employment); Simon Kaja Experimentica Ltd., Code C (Consultant/Contractor), Experimentica Ltd., K&P Scientific LLC, Code F (Financial Support), Experimentica Ltd., K&P Scientific LLC, Code I (Personal Financial Interest), eyeNOS Inc., Code P (Patent), Experimentica Ltd., K&P Scientific LLC, Code R (Recipient), Experimentica Ltd., K&P Scientific LLC, Code S (non-remunerative); Giedrius Kalesnykas Experimentica, Code E (Employment); Robert Scoffin Cresset, Code E (Employment), Cresset, Code O (Owner); Justine O'Brien None
  • Footnotes
    Support  Irish Research Council Enterprise Partnership Scheme Postgraduate Scholarship EPSPG/2020/29. European Union’s Horizon 2020 Research and Innovation programme under grant agreement No 101007931
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 680 – F0134. doi:
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      Breandan N Kennedy, John Fehilly, Marc Cerrada-Gimenez, Simon Kaja, Giedrius Kalesnykas, Robert Scoffin, Justine O'Brien; Visual behaviour-based screening of a randomised chemical library identifies small molecules that restore vision.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):680 – F0134.

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

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Abstract

Purpose : Retinal and macular degenerations are conditions with progressive photoreceptor or retinal pigment epithelium (RPE) dysfunction resulting in blindness. Most patients lack effective treatments to preserve vision. Efficient and effective phenotypic screening of randomised compound libraries can uncover first-in-class drugs. Here, using a bespoke drug discovery workflow we identify drugs rescuing vision.

Methods : Phenotypic drug discovery was performed on the atp6v0e1UCD6 zebrafish model of impaired vision screening a Chembridge DIVERSet® randomised compound library. 80 compounds were combined into 18 orthogonal drug pools for plate testing. Visual behaviour was analysed at 5 dpf by optokinetic response.

Results : Proof-of-concept assays validated orthogonal drug pooling as appropriate for optokinetic response screening. The orthogonal pooling protocol successfully detected visual rescue of atp6v0e1UCD6 in Tubastatin A spiked pools (positive control) with 3-fold visual improvement. Of the 720 compounds screened, 86% of pools did not alter vision and 8% of pools showed overt toxicity. Two hit compounds were identified. UCD-OPGG-2C is a benzenedicarboxylic acid and dimethyl ester with a molecular weight (MW) of 277.28 UCD-OPGG-3E is a cyclohexanecarboxamide with a MW of 265.79. Re-purchased UCD-OPGG-3E elicited a significant (p< 0.025), two-fold improvement in vision in atp6v0e1UCD6 larvae.

Conclusions : We developed a novel workflow to efficiently detect compounds restoring vision in zebrafish. Future experiments will analyse retinal histology, and ocular safety and efficacy in rodent models. Computational approaches will identify novel structural analogues of UCD-OPGG-2C and UCD-OPGG-3E.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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