A novel corticosteroid with ROCK inhibitory activity can reduce ocular inflammation and lower IOP in animal models

Abstract

Purpose : Corticosteroids are invaluable for controlling inflammation and preventing loss of vision in various ocular conditions. Unfortunately, they have considerable side effects that are themselves a risk for vison loss, including steroid-induced glaucoma. While the mechanisms by which steroids cause elevated intraocular pressure (IOP) are not well understood, fibrosis and collagen deposition in the trabecular meshwork (TM) have been described in patients with steroid-induced glaucoma. Rho kinase (ROCK) inhibition has been shown to impair deposition of collagen and fibronectin in cultured TM cells. Importantly, ROCK inhibition has also been shown to lower IOP by improving aqueous humor (AH) outflow through the TM. We postulate that ROCK inhibition concomitant with steroid use may decrease the risk of elevated IOP associated with ophthalmic steroid use and utilize a novel compound to explore this hypothesis.

Methods : A novel compound consisting of triamcinolone linked to the ROCK inhibitor AR-13503, the active metabolite of netarsudil, was generated. Its distribution in ocular target tissues following topical administration was determined by mass spectrometry. The endotoxin-induced uveitis (EIU) and allergic eye disease (AED) models were employed to assess the ROCKi-steroid anti-inflammatory activity. The compound’s in vivo ROCK inhibitory activity was determined empirically by measuring IOP in rabbits treated topically.

Results : The ROCKi-steroid reached ocular tissues of interest following topical treatment, delivering triamcinolone and AR-13503 to tissues at physiologically relevant levels. Treatment with the ROCKi-steroid reduced neutrophil infiltration dose-dependently in the EIU model and inhibited the adaptive response in AED. Significant reductions in inflammation compared to vehicle controls were observed with doses of the ROCKi-steroid that were >20 times lower than the clinically relevant 0.1% dexamethasone. IOP was reduced in rabbits treated with the ROCKi-steroid topically.

Conclusions : A novel ROCKi-steroid (AR-13503-triamcinolone) provided both anti-inflammatory and IOP-lowering activity in animal models. Simultaneous delivery of a steroid with a ROCK inhibitor in this manner deserves further study to evaluate the potential to reduce the risk of steroid-induced glaucoma in patients who require chronic steroid treatment.

This is a 2020 ARVO Annual Meeting abstract.