Developing novel TRPV4 antagonists for the treatment of glaucoma

Abstract

Purpose : A single target in the conventional outflow pathway has been approved for glaucoma treatment but the ubiquitous ocular distribution of Rho kinases (ROCKs) is not ideal in terms of specificity and potential side effects. To obviate this, we sought to determine the upstream driver of ROCK in the trabecular meshwork (TM) and Schlemm’s canal and tested the efficacy of its modulation as an IOP lowering strategy in acute and chronic models of ocular hypertension.

Methods : Novel anti-TRPV4 compounds were tested by calcium imaging and electrophysiology in vitro in overexpressing HEK293 (HEK-V4OE) cells and primary trabecular meshwork (pTM) cells. IOP was elevated in mice acutely via cannulation or chronically with the microbead occlusion method. IOP lowering was also tested in beagles that express the ADAMTS10 mutation. IOP was measured tonometrically for roughly 24 hrs (mice) or a week (dogs) following topical antagonist administration.

Results : The calcium-permeable stretch-activated channel TRPV4 was identified as the upstream driver of mechanically induced ROCK activation in the TM. SMC-0151 and SMC-0155 inhibited TRPV4 activity at picomolar concentrations, with dose-dependent suppression of agonist-evoked responses. SMCs, but not the commercial antagonist HC067047, lowered IOP in the acute mouse model. Intraocular injection and topical administration significantly lowered IOP in the chronic model. The IOP-lowering effect in dogs was facilitated by increasing the drug concentration.

Conclusions : We demonstrate that TRPV4 and calcium drive mechanically-induced Rho pathway signaling in the TM. Novel, cornea-permeant TRPV4 antagonists were developed as effective reducers of intraocular pressure in two animal models of glaucoma. These results shed light onto the basic mechanisms of IOP-induced TM injury and expand the roster of potential anti-glaucoma strategies and targets.

This is a 2021 ARVO Annual Meeting abstract.