The role of EP 2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

Autor: Bertrand JA; Dept. of Bioengineering, Imperial College London, London, UK., Woodward DF; Dept. of Bioengineering, Imperial College London, London, UK.; JeniVision Inc, Suite 200, Irvine, California, USA., Sherwood JM; Dept. of Bioengineering, Imperial College London, London, UK., Wang JW; JeniVision Inc, Suite 200, Irvine, California, USA., Overby DR; Dept. of Bioengineering, Imperial College London, London, UK d.overby@imperial.ac.uk.
Jazyk: angličtina
Zdroj: The British journal of ophthalmology [Br J Ophthalmol] 2021 Nov; Vol. 105 (11), pp. 1610-1616. Date of Electronic Publication: 2020 Nov 25.
DOI: 10.1136/bjophthalmol-2020-317762
Abstrakt: 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 EP 2 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 EP 2 receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP 2 receptors.
Methods: The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP 2 receptor knock-out mice (B6.129- Ptger2 tm1Brey /J; EP 2 KO). 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 EP 2 receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP 2 KO mice, but in littermate SI-OHT EP 2 WT 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 EP 2 receptor dependent.
Competing Interests: 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.
(© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze: MEDLINE
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