Rho-associated kinase inhibitors: A novel glaucoma therapy

Inoue, Toshihiro; Tanihara, Hidenobu

doi:10.1016/j.preteyeres.2013.05.002

Cited by 141 publications

(113 citation statements)

References 116 publications

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“…Accumulating evidence suggests that ROCK participates in the regulation of aqueous outflow, including pharmacological data from clinical trials showing that ROCK inhibitors decrease intraocular pressure and demonstrate beneficial effects in glaucoma patients (Inoue and Tanihara, 2013). ROCK gene polymorphisms were thus recently investigated in primary open-angle glaucoma, the most common form of glaucoma (Demiryürek et al, 2015).…”

Section: Glaucomamentioning

confidence: 99%

“…Lowering intraocular pressure is the only therapeutic strategy shown to be effective in the treatment of glaucoma. Accumulating preclinical evidence shows that activation of RhoA/ROCK in the outflow pathway (trabecular meshwork, Schlemm canal) reduces aqueous humor outflow, thereby increasing intraocular pressure (Inoue and Tanihara, 2013). By contrast, ROCK inhibition increases aqueous humor outflow and decreases intraocular pressure, an effect mainly attributed to the relaxing action of ROCK inhibitors on smooth muscle-like trabecular meshwork cells shown to express both ROCK1 and ROCK2 .…”

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

“…Several phase 1 and phase 2 clinical trials have been conducted to assess the safety and efficacy of topical application of various ROCK inhibitors in patients with glaucoma or ocular hypertension. Although results from some of these studies have not yet been published (Table 6), clinical studies of K-115 (ripasudil; Tanihara et al, 2013Tanihara et al, , 2015 and AR-13324 [XXX] (Bacharach et al, 2015) demonstrated safety and efficacy of once-or twice-daily administration of the inhibitor to decrease intraocular pressure. A phase 3 clinical trials for AR-13324 is in progress (Table 6).…”

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

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Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

167

133

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Section: Glaucomamentioning

confidence: 99%

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

See 1 more Smart Citation

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

167

133

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“…12,13 These molecules work through inhibition of the actin cytoskelon contractile tone of smooth muscle thereby relaxing the trabecular meshwork and improving outflow facility through the conventional pathway. Several published studies in the U.S., Europe, and Japan have shown documented enhanced outflow of aqueous in animal and human eyes and relaxation of pre contracted TM.…”

Section: Rhokinase Inhibitorsmentioning

confidence: 99%

“…On activation by binding to GTP (guanosine triphosphate), Rho activates it's effector molecules ROCK (rhokinase) which polymerize actin fibers inducing vasoconstriction and decrease cell migration. 13 ROCK inhibitors depolymerize filamentous actin leading to enhanced TM outflow presumably by wider empty spaces in the juxtacanalicular region and increased vacuoles in endothelial cells.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Rhokinase Inhibitors novel Potential Treatment Modality for Glaucoma

Dhillon¹

2016

DJO

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Rhokinase inhibitors is a new class of drug under trial that improve the outflow facility through conventional path way by inhibiting the contractile tone of actin cytoskeleton. They additionally protect trabecular meshwork from oxidative stress, improve Optic Nerve head blood flow, facilitate corneal endothelium wound healing, increase ganglion cell survival and reduce scarring in glaucoma surgery.

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Prevention of Nocturnal Elevation of Intraocular Pressure by Gene Transfer of Dominant-Negative RhoA in Rats

et al. 2015

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IMPORTANCEWe developed a gene transfer tool for the control of nocturnal elevated intraocular pressure (IOP).OBJECTIVE To demonstrate that inhibiting the trabecular meshwork RhoA pathway by delivering a mutated, dominant-negative RhoA gene (dnRhoA) carried inside a long-expressing recombinant virus would reduce nocturnal elevated IOP in a living animal. DESIGN AND SETTINGWe generated an optimized recombinant viral molecule by inserting a mutated RhoA complementary DNA with a translation enhancer-promoter into a specially designed plasmid containing mutated viral terminal repeats. We then generated the virus particle, self-complementary adeno-associated virus serotype 2 carrying the mutated gene (scAAV2.dnRhoA) and assessed its function in vitro by infecting primary human trabecular meshwork cells and in vivo by injecting living rats intracamerally with therapeutic and control viruses. Three different models of 12-hour light and dark cycles were used. Viruses were injected when animals showed the circadian dark IOP elevation. The IOP measurements were conducted with a tonometer at 2 to 4 hours after onset of the nocturnal and diurnal cycles. Values at preinjection time were used as baselines. Animals were euthanized at 4 to 8 weeks after injection.EXPOSURES Intraocular injection of rodent eyes with the recombinant viral vector scAAV2.dnRhoA. MAIN OUTCOMES AND MEASURESNocturnal elevation of IOP blocked for prolonged periods by transferred RhoA gene.RESULTS By visual inspection, human trabecular meshwork cells infected with scAAV2.dnRhoA showed diminished stress fiber formation. Living rats exhibited a circadian IOP cycle that could be reset by adjusting light conditions to facilitate light and dark nocturnal IOP studies. A single-dose injection of scAAV2.dnRhoA into the rat eyes prevented elevation of IOP during the nocturnal cycle for at least 4 weeks (mean [SE], 9.2 [0.2] mm Hg light IOP and 9.6 [0.4] mm Hg dark IOP), while control eyes showed a significantly higher IOP over baseline (9.5 [0.4] mm Hg light IOP and 13.5 [0.3] mm Hg dark IOP). CONCLUSIONS AND RELEVANCETo our knowledge, this is the first example of a gene transfer strategy that prevents nocturnal IOP elevation in living animals for prolonged periods. Inhibiting the RhoA pathway upstream of Rho kinase with a safe gene drug could provide a new enhanced treatment for long-term management of elevated nocturnal IOP.

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Rho-associated kinase inhibitors: A novel glaucoma therapy

Cited by 141 publications

References 116 publications

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Rhokinase Inhibitors novel Potential Treatment Modality for Glaucoma

Prevention of Nocturnal Elevation of Intraocular Pressure by Gene Transfer of Dominant-Negative RhoA in Rats

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