Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study

Sit, Arthur J.; Gupta, Divakar; Kazemi, Arash; McKee, Hayley; Challa, Pratap; Liu, Katy C.; Lopez, Jae; Kopczynski, Casey; Heah, Theresa

doi:10.1016/j.ajo.2021.01.019

Cited by 36 publications

(22 citation statements)

References 41 publications

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“…In contrast, the FDA-approved Rhoassociated kinase inhibitor (ROCKi) netarsudil, the active ingredient in Rhopressa ™ , increases outflow through the stiffened TM via reducing TM contraction as a function of ECM-focal adhesion and actin stress fiber disassembly (14)(15)(16)(17)(18). The ability of netarsudil to improve outflow facility has been demonstrated in preclinical animal studies (19,20), in an ex vivo perfusion study of human donor eyes (21), and in two human clinical studies (22,23). In contrast, only a single study to date has investigated netarsudil's effect on normal and glaucomatous human TM (HTM) cell actin remodeling in vitro using live cellimaging (24).…”

Section: Introductionmentioning

confidence: 99%

Effects of Netarsudil-Family Rho Kinase Inhibitors on Human Trabecular Meshwork Cell Contractility and Actin Remodeling Using a Bioengineered ECM Hydrogel

et al. 2022

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Interactions between trabecular meshwork (TM) cells and their extracellular matrix (ECM) are critical for normal outflow function in the healthy eye. Multifactorial dysregulation of the TM is the principal cause of elevated intraocular pressure that is strongly associated with glaucomatous vision loss. Key characteristics of the diseased TM are pathologic contraction and actin stress fiber assembly, contributing to overall tissue stiffening. Among first-line glaucoma medications, the Rho-associated kinase inhibitor (ROCKi) netarsudil is known to directly target the stiffened TM to improve outflow function via tissue relaxation involving focal adhesion and actin stress fiber disassembly. Yet, no in vitro studies have explored the effect of netarsudil on human TM (HTM) cell contractility and actin remodeling in a 3D ECM environment. Here, we use our bioengineered HTM cell-encapsulated ECM hydrogel to investigate the efficacy of different netarsudil-family ROCKi compounds on reversing pathologic contraction and actin stress fibers. Netarsudil and all related experimental ROCKi compounds exhibited significant ROCK1/2 inhibitory and focal adhesion disruption activities. Furthermore, all ROCKi compounds displayed potent contraction-reversing effects on HTM hydrogels upon glaucomatous induction in a dose-dependent manner, relatively consistent with their biochemical/cellular inhibitory activities. At their tailored EC50 levels, netarsudil-family ROCKi compounds exhibited distinct effect signatures of reversing pathologic HTM hydrogel contraction and actin stress fibers, independent of the cell strain used. Netarsudil outperformed the experimental ROCKi compounds in support of its clinical status. In contrast, at uniform EC50-levels using netarsudil as reference, all ROCKi compounds performed similarly. Collectively, our data suggest that netarsudil exhibits high potency to rescue HTM cell pathobiology in a tissue-mimetic 3D ECM microenvironment, solidifying the utility of our bioengineered hydrogel model as a viable screening platform to further our understanding of TM pathophysiology in glaucoma.

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Section: Introductionmentioning

confidence: 99%

Effects of Netarsudil-Family Rho Kinase Inhibitors on Human Trabecular Meshwork Cell Contractility and Actin Remodeling Using a Bioengineered ECM Hydrogel

et al. 2022

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“…Curiously, netarsudil, a rho kinase inhibitor which causes vasodilation, decreases EVP in both animals and humans. 37 – 39 Nevertheless, it is reasonable to expect that topical phenylephrine, a sympathomimetic agent with primary alpha-1 adrenergic activity known to act directly on vascular smooth muscle resulting in vasoconstriction, 40 , 41 would affect EVP. Aqueous humor suppression with timolol or acetazolamide does not appear to affect EVP.…”

Section: Discussionmentioning

confidence: 99%

Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes

Kazemi

McLaren

Sit

2021

Invest. Ophthalmol. Vis. Sci.

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Purpose Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects. Methods Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t -tests. Results IOP increased 15 minutes after instillation of phenylephrine in both treated ( P = 0.001) and control eyes ( P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes ( P = 0.8) but decreased significantly at 60 minutes ( P < 0.001). In control eyes, there was no change in EVP at any time ( P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine. Conclusions IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

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“…The pathogenesis of glaucoma is still unknown, and there is no clear clinical treatment plan. Currently, local medication is mostly used for symptomatic treatment [3], in order to delay or prevent the onset of glaucoma, but the efficacy is a little less than that, and the side effects are obvious. In this case, taking Jingming (BL1) near and Guangming (GB37) far is the main method, supplemented by relevant points, to treat teenagers with high ocular pressure, and the curative effect is good.…”

Section: Introductionmentioning

confidence: 99%

Acupuncture at Jingming and Guangming Points Mainly Treats Adolescents with Ocular Hypertension

2022

JCMP

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Ocular hypertension is a disease characterized by continuous increase of intraocular pressure, open angle of chamber, no visual field defect, and normal optic nerve fibers and papilla. Teenagers are in the stage of physical and mental development, and the pressure is characterized by instability, which is characterized by high values measured by applanation tonometer for many times in a period of time, which is called "adolescent ocular hypertension". The pathogenesis of glaucoma is still unclear, and there is no clear treatment plan in clinic. At present, topical symptomatic treatment is mostly used to delay or prevent the onset of glaucoma, but the curative effect is a little poor and the side effects are obvious. In this case, acupuncture is used to treat adolescent ocular hypertension, which is mainly based on near-eyes and far-eyes, supplemented by relevant acupoints, and the effect is good.

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Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study

Cited by 36 publications

References 41 publications

Effects of Netarsudil-Family Rho Kinase Inhibitors on Human Trabecular Meshwork Cell Contractility and Actin Remodeling Using a Bioengineered ECM Hydrogel

Effects of Netarsudil-Family Rho Kinase Inhibitors on Human Trabecular Meshwork Cell Contractility and Actin Remodeling Using a Bioengineered ECM Hydrogel

Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes

Acupuncture at Jingming and Guangming Points Mainly Treats Adolescents with Ocular Hypertension

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