Netarsudil (NT) restores trabecular meshwork (TM) function/stiffness and reduces IOP in steroid-induced ocular hypertension (OHT)

Abstract

Purpose : We investigated the effects of NT, a recently approved rho kinase inhibitor, on IOP and several aspects of TM function in steroid OHT in both mice and humans.

Methods : In wild-type C57BL/6 mice (both sexes, 3-6 months), OHT was induced by repeated periocular bilateral injection of nanoparticles entrapping dexamethasone (DEX-NPs), as previously described (Li+, PNAS, 2019). After 3 wks, mice received daily NT or placebo (PL) unilaterally for 4 days. IOP was measured throughout, and at the end of the experiment we measured outflow facility, processed eyes for TM histology, and/or determined TM stiffness by OCT imaging plus engineering structural analysis (Li+, PNAS, 2019). In humans, a retrospective chart review (search criteria: “netarsudil” + ICD-10 codes for “steroid responder” and “steroid glaucoma”) identified 10 eyes of 9 patients with steroid glaucoma whose IOPs were poorly controlled on multiple glaucoma medications and subsequently received NT.

Results : DEX-NPs elevated IOP in mice. After 3 wks of DEX-NPs, NT rapidly lowered IOP within one day, returning IOP to near baseline level within 4 days (elevation of IOP compared to baseline = 8.19 ± 0.46 mmHg in PL-treated vs. 2.69 ± 0.47 mmHg in NT-treated eyes; p < 10^-4; n=17-19/group). NT also increased outflow facility by 33% vs. PL-treated eyes, and the observed IOP lowering was quantitatively explained by measured facility changes. NT also decreased fibrotic markers in TM (amount of basement membrane material underlying the inner wall of Schlemm’s canal, fibronectin and α-smooth muscle actin in the TM). Importantly, 4 days of NT essentially completely reversed TM stiffening due to steroid (TM stiffness in PL-treated eyes receiving steroid = 61 kPa vs. 22 kPa after NT treatment; cf. previously-measured stiffness of 29kPa in naïve eyes). In patients with steroid glaucoma, IOP before NT treatment was 26.1 ± 7.0 mmHg, which decreased by an average of 8.6 mmHg after 1 month of NT treatment (p < 0.0005).

Conclusions : We conclude that NT acts on the TM to reverse ocular hypertension due to steroids. In a mouse model of steroid OHT, this anti-hypertensive effect is accompanied by rapid structural changes in the TM, including TM “softening” and reduction of fibrosis. In steroid glaucoma patients refractory to multiple therapies, NT significantly lowers IOP. Further study of NT in steroid glaucoma is indicated.

This is a 2020 ARVO Annual Meeting abstract.