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The role of EP2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1
  1. Jacques A Bertrand1,
  2. David F Woodward1,2,
  3. Joseph M Sherwood1,
  4. Jenny W Wang2,
  5. Darryl R Overby1
  1. 1Dept. of Bioengineering, Imperial College London, London, UK
  2. 2JeniVision Inc, Suite 200, Irvine, California, USA
  1. Correspondence to Dr Darryl R Overby, Department of Bioengineering, Imperial College London, London, UK; d.overby{at}imperial.ac.uk

Abstract

Background A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP2 receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP2 receptors.

Methods The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP2 receptor knock-out mice (B6.129-Ptger2tm1Brey/J; EP2KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.

Results Both the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP2KO mice, but in littermate SI-OHT EP2WT control mice, JV-GL1 statistically significantly lowered IOP for 4–6 days.

Conclusions Both the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP2 receptor dependent.

  • glaucoma
  • intraocular pressure
  • pharmacology
  • treatment medical
  • biochemistry

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Footnotes

  • Twitter @TheSherwoodLab

  • Contributors Conception and design: DFW, JWW, DRO. Data collection: JAB. Analysis and interpretation: JAB, JMS, DRO. Manuscript preparation: JAB, DFW. Overall responsibility: DRO, JWW. Final approval: DRO.

  • Funding The authors would like to thank BrightFocus Foundation (G2015145), National Institutes of Health (EY022359) and the Fight for Sight Foundation (1858).

  • Competing interests DFW and JWW are co-owners of JeniVision Inc, a biotechnology start-up that holds a patent on JV-GL1 and supplied material support for these studies.

  • Patient consent for publication Not required.

  • Ethics approval All procedures on living mice were carried out in compliance with the Imperial College Statement for Use of Animals in Research, under UK Home Office project license 70/9064. All animal care and experimental protocols adhered to (1) the US National Research Council’s Guide for the Care and Use of laboratory animals, (2) the ARVO guidelines and (3) the BJP guidelines for experiments involving animals and animal tissues.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data and analyses are available by contacting the following at their ORCID numbers, as follows: 0000-0001-9894-75150000-0002-4402-9767.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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