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Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.

ABSTRACT: In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

SUBMITTER: Tanna AP

PROVIDER: S-EPMC6188806 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.

Tanna Angelo P AP Johnson Mark M

Ophthalmology 20180712 11

In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the c ...[more]

PMID: 30007591

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Project description:PurposePrimary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS).DesignComparative series.ParticipantsOne thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study.MethodsSamples of DNA were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using analyses of variance. The 2 largest subgroups, non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%), also were analyzed separately. The probability of glaucoma developing over the course of the OHTS was compared between participants stratified for transmembrane and coiled-coil domains 1 (TMCO1) risk alleles using Kaplan-Meier and Cox proportional hazards analyses.Main outcome measuresAssociation of POAG with known genetic factors.ResultsNo association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls (P = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of glaucoma developing than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increased relative risk comparable with that of some previously analyzed clinical measures (i.e., intraocular pressure).ConclusionsThe size of the OHTS cohort and its composition of 2 large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that long have been associated with glaucoma.

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Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.

Publications

Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.

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