loading page

The ultralong-acting intraocular pressure reduction produced by JV-GL1 is mediated entirely by prostanoid EP2 receptors, according to gene deletion
  • +3
  • Jacques Bertrand,
  • David Woodward,
  • Joseph Sherwood,
  • Robert Coleman,
  • Jenny Wang,
  • Darryl Overby
Jacques Bertrand
Imperial College London
Author Profile
David Woodward
Imperial College London
Author Profile
Joseph Sherwood
Imperial College London
Author Profile
Robert Coleman
private consultant
Author Profile
Jenny Wang
JeniVision Inc.
Author Profile
Darryl Overby
Imperial College London
Author Profile

Abstract

BACKGROUND AND PURPOSE: A single dose of JV-GL1 lowers intraocular pressure (IOP) for a week according to previous studies on non-human primates. This highly protracted effect did not correlate with its ocular bio-disposition, where the drug was undetectable inside the eye after only one day post-dosing. Our current studies were intended to determine the role of EP2 receptors in mediating the long-term ocular hypotensive activity of JV-GL1 and utilized mice deficient in EP2 receptors. EXPERIMENTAL APPROACH: The protracted intraocular pressure 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. Intraocular pressure was measured tonometrically under general anesthesia. Aqueous humor outflow facility was measured ex vivo using the iPerfusion system 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. KEY RESULTS: In SI-OHT, JV-GL1 did not lower IOP in EP2 KO mice. However, in WT mice with SI-OHT, JV-GL1 lowered IOP for 4-6 days. JV-GL1 did not alter outflow facility in WT mice at 3 days after topical administration. CONCLUSIONS AND IMPLICATIONS: The long-term effect of JV-GL1 on IOP in the SI-OHT model of glaucoma is EP2 receptor dependent. Such protracted activity of a single dose of a small molecule (JV-GL1) is unprecedented. Future studies on JV-GL1 may eventually lead to “once-weekly” small molecules, with reduced drug prices and better disease control.