ROCK inhibitors in glaucoma medical treatment

Abstract

AbstractRho kinase inhibitors are a novel advancement in glaucoma medical treatment and have been recently approved for instruction in the market in fixed combination with the prostaglandin analogue Latanoprost. They have a novel mechanism of action based on their ability to improve humour aqueous outflow through the conventional trabecular meshwork pathway.Rho family proteins are GTPases that localize in the intracellular side of plasma membrane and are activated by several plasma membrane signal receptors, including TGF‐β and hormones.Activated Rho then activates Rho‐associated protein kinases which further transmit the stimulus to downstream effectors. The whole pathway is involved in several cellular activities, including actin cytoskeleton organization, cell adhesion and motility, proliferation and apoptosis, and remodelling of the ECM. ROCKs mediate pro‐fibrotic processes in many tissues and pathological conditions. In cultured human TM cells, exposure to a ROCK inhibitor caused retraction and rounding of cell bodies, as well as disruption of actin bundles and impaired focal adhesion formation. ROCKs have been associated when administered topically to a reduction in episcleral venous pressure that might contribute to their ocular hypotensive effects.MERCURY‐3, was a prospective, randomized, double‐masked, active‐controlled study to assess the efficacy, safety, and tolerability of the ROCK inhibitor netarsudil 0.02% in fixed combination with latanoprost 0.005% compared with the fixed combination of bimatoprost 0.03%/timolol 0.5%.The results of the study showed non inferiority of the netarsudil fixed combination despite a slightly worse local tolerability profile.Current management approaches aim to reduce IOP but do not tackle the principal site of increased outflow resistance that is the TM. ROCK inhibition shows for the first time the ability for directly modulating the TM permeability and represents a new clinical treatment for glaucoma.