ROCK Inhibitor (Ripasudil) as Coadjuvant After Descemetorhexis Without an Endothelial Graft

Galvis, Virgilio; Tello, Alejandro; Fuquen, Johanna P.; Rodríguez-Barrientos, Carlos A.; Grice, Juan

doi:10.1097/ico.0000000000001381

Cited by 5 publications

(1 citation statement)

References 12 publications

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“…It has been reported to possess similar efficacy comparable to Y-27632 [9]. Others have shown, through in vivo experimental outcomes and case reports involving endothelial wound recovery, that the optimal dose for Ripasudil should be at least twice the dosage recommended for glaucoma treatment [13,61,62]. In addition, Ripasudil has been reported to induce rosette-like changes to the corneal endothelial cells when applied in normal corneas [63], and was associated with multiple side effects including blepharitis, bowel disorders, and hyperemia, leading to its discontinuation [64].…”

Section: Discussionmentioning

confidence: 99%

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells

Peh

Bandeira

Neo

et al. 2023

Cells

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(1) Rho-associated coiled-coil protein kinase (ROCK) signaling cascade impacts a wide array of cellular events. For cellular therapeutics, scalable expansion of primary human corneal endothelial cells (CECs) is crucial, and the inhibition of ROCK signaling using a well characterized ROCK inhibitor (ROCKi) Y-27632 had been shown to enhance overall endothelial cell yield. (2) In this study, we compared several classes of ROCK inhibitors to both ROCK-I and ROCK-II, using in silico binding simulation. We then evaluated nine ROCK inhibitors for their effects on primary CECs, before narrowing it down to the two most efficacious compounds—AR-13324 (Netarsudil) and its active metabolite, AR-13503—and assessed their impact on cellular proliferation in vitro. Finally, we evaluated the use of AR-13324 on the regenerative capacity of donor cornea with an ex vivo corneal wound closure model. Donor-matched control groups supplemented with Y-27632 were used for comparative analyses. (3) Our in silico simulation revealed that most of the compounds had stronger binding strength than Y-27632. Most of the nine ROCK inhibitors assessed worked within the concentrations of between 100 nM to 30 µM, with comparable adherence to that of Y-27632. Of note, both AR-13324 and AR-13503 showed better cellular adherence when compared to Y-27632. Similarly, the proliferation rates of CECs exposed to AR-13324 were comparable to those of Y-27632. Interestingly, CECs expanded in a medium supplemented with AR-13503 were significantly more proliferative in (i) untreated vs. AR-13503 (1 μM; * p < 0.05); (ii) untreated vs. AR-13503 (10 μM; *** p < 0.001); (iii) Y-27632 vs. AR-13503 (10 μM; ** p < 0.005); (iv) AR-13324 (1 μM) vs. AR-13503 (10 μM; ** p < 0.005); and (v) AR-13324 (0.1 μM) vs. AR-13503 (10 μM; * p < 0.05). Lastly, an ex vivo corneal wound healing study showed a comparable wound healing rate for the final healed area in corneas exposed to Y-27632 or AR-13324. (4) In conclusion, we were able to demonstrate that various classes of ROCKi compounds other than Y-27632 were able to exert positive effects on primary CECs, and systematic donor-match controlled comparisons revealed that the FDA-approved ROCK inhibitor, AR-13324, is a potential candidate for cellular therapeutics or as an adjunct drug in regenerative treatment for corneal endothelial diseases in humans.

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Section: Discussionmentioning

confidence: 99%

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells

Peh

Bandeira

Neo

et al. 2023

Cells

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Effect of Rho-associated kinase inhibitor on human corneal endothelial cell apoptosis

Achiron

Feldman

Karmona

et al. 2020

J Cataract Refract Surg

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Purpose: To evaluate whether exposure to Rho-associated protein kinase (ROCK) inhibitor will promote human-cultured corneal endothelial cells (CECs) survival in a commercial storage medium. Setting: Edith Wolfson Medical Center, Holon, and Sheba Medical Center, Tel Hashomer, Israel. Design: Experimental study. Methods: Fragments of human donor corneolimbal rings were stored in commercial storage media for 1 week, half with the addition of 10 μM ROCK inhibitor (Y-27632). Evaluation of CECs for early and late apoptosis\necrosis rates was performed using anti-human CD166 antibody and flow cytometric double staining analysis of propidium iodide and Annexin V. Results: CECs of 6 corneolimbal rings demonstrated a reduced early apoptosis rate (4.35% ± 1.07% vs 12.18% ± 5.5%, P = .026) and a reduced late apoptosis\necrosis rate (5.5% ± 2.39% vs 9.43% ± 2.61%, P = .004) compared with control. Subsequently, the rate of apoptotic CECs expressing ROCK was significantly lower in cells exposed to ROCK inhibitor compared with cells that were not (19.01% ± 4.17 vs 30.42% ± 4.27, P < .001). Conclusions: ROCK inhibitor reduced endothelial cell loss in vitro and might be used to limit or slow CEC loss in donor corneal tissue during eye banking. This might be a promising new method for promoting future graft survival.

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Challenges of obtaining cultured corneal endothelial cells for regenerative purposes

Ostrovski,

Borzenok,

Malyugin

et al. 2024

RJTAO

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Human posterior corneal epithelium (corneal endothelium) has limited proliferative activity both in vivo and in vitro. Disease or dysfunction in these cells leads to impaired corneal transparency of varying degrees of severity, up to blindness. Currently, the only effective standard treatment for corneal endothelial dysfunction is transplantation of donor cornea that contains a pool of healthy and functionally active cells. However, there is a global shortage of donor corneas, which has led to an unmet clinical need and the fact that only 1 patient out of 10 in need receives surgical treatment. Therefore, creation of cellular constructs and artificial human corneas containing healthy endothelium is a very urgent challenge facing modern ophthalmic transplantology. This review presents the current state of affairs, challenges and prospects for obtaining cultured corneal endothelial cells (CECs) in vitro for transplantation purposes.

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ROCK Inhibitor (Ripasudil) as Coadjuvant After Descemetorhexis Without an Endothelial Graft

Cited by 5 publications

References 12 publications

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells

Effect of Rho-associated kinase inhibitor on human corneal endothelial cell apoptosis

Challenges of obtaining cultured corneal endothelial cells for regenerative purposes

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