Purpose:Descemet stripping only (DSO) is a promising surgical option for select patients with Fuchs endothelial dystrophy (FED). There is growing support for the use of topical Rho-associated protein kinase inhibitors (ROCKi) to optimize DSO outcomes. However, in many settings, ROCKi are either unavailable or not approved to treat corneal diseases. This study sought to characterize patient outcomes after DSO in the absence of ROCKi and potentially broaden the settings where DSO can be offered to patients.Methods:Single-center retrospective case series of 15 eyes/11 patients (66 years; 52–74) that underwent DSO, alone or combined with cataract surgery, by one surgeon between August 2020 and January 2023. Patients included in analyses had FED with central guttae, no clinical evidence of corneal edema, and a clinically healthy peripheral corneal endothelium.Results:Mean follow-up time was 14 months (2–34). Fourteen of 15 eyes achieved corneal clearance (93.3%). Mean time to clearance was 8.5 weeks (3–23). Eleven eyes (73%) achieved corrected distance visual acuity of ≤0.2 with a significant postoperative improvement at 4 to 8 months (P < 0.05) and sustained improvements at >12 months. No significant astigmatism was introduced by the procedure. Two eyes developed cystoid macular edema postoperatively. A trend toward earlier clearance was observed in the <65 years old group.Conclusions:Despite a longer time to corneal clearance in this cohort compared with the few studies using ROCKi, the overall success rate and visual outcomes for the patients in our cohort supports the use of DSO in settings where ROCKi are not readily available.

01 Sep 2024·Current Opinion in Ophthalmology

Emerging alternatives to keratoplasty for corneal endothelial cell dysfunction

Review

Author: Kaufman, Ron ; Jun, Albert S

Purpose of reviewWhile effective for treating endothelial dysfunction, keratoplasty has shortcomings including limited access to donor tissue for much of the world. Thus, alternative strategies are under development. This review explores the main advancements achieved in this field during 2022–2023.Recent findingsRecent publications further support the validity of intracameral cultivated allogeneic endothelial cell injection and Descemet stripping only, while emphasizing the benefits of adjunctive Rho-associated kinase inhibitor (ROCKi) therapy. New donor-independent artificial implants, such as EndoArt, show favorable results. Multiple pharmacologic agents, especially ROCKi, show promise as monotherapies, yet none are currently approved for human treatment. Multiple regenerative and genetic therapies are being investigated but all are still in preclinical stages.SummaryA plethora of innovative alternatives to keratoplasty for endothelial disease is in development. Among these, surgical methods are still the mainstay of treatment and closest to clinical application, though further studies to establish their benefits over keratoplasty are needed. Albeit promising, pharmacologic, regenerative, and genetic approaches require validation and are farther from clinical application.

01 May 2024·Biomedicine & Pharmacotherapy

“Keep on ROCKIn”: Repurposed ROCK inhibitors to boost corneal endothelial regeneration

Article

Author: Van den Bogerd, Bert ; Kotulova, Jana ; Le Compte, Maxim ; De La Hoz, Edgar Cardenas ; Vercammen, Hendrik ; Koppen, Carina ; Deben, Christophe ; Ondra, Martin ; Witters, Charissa ; Ní Dhubhghaill, Sorcha ; Hajdúch, Marián ; Jecmenova, Katerina

The global shortage of corneal endothelial graft tissue necessitates the exploration of alternative therapeutic strategies. Rho-associated protein kinase inhibitors (ROCKi), recognized for their regenerative potential in cardiology, oncology, and neurology, have shown promise in corneal endothelial regeneration. This study investigates the repurposing potential of additional ROCKi compounds. Through screening a self-assembled library of ROCKi on B4G12 corneal endothelial cells, we evaluated their dose-dependent effects on proliferation, migration, and toxicity using live-cell imaging. Nine ROCKi candidates significantly enhanced B4G12 proliferation compared to the basal growth rate. These candidates were further assessed for their potential to accelerate wound closure as another indicator for tissue regeneration capacity, with most demonstrating notable efficacy. To assess the potential impact of candidate ROCKi on key corneal endothelial cell markers related to cell proliferation, leaky tight junctions and ion efflux capacity, we analyzed the protein expression of cyclin E1, CDK2, p16, ZO-1 and Na⁺/K⁺-ATPase, respectively. Immunocytochemistry and western blot analysis confirmed the preservation of corneal endothelial markers post-treatment with ROCKi hits. However, notable cytoplasm enlargement and nuclear fragmentation were detected after the treatment with SR-3677 and Thiazovivin, indicating possible cellular stress. In compared parameters, Chroman-1 at a concentration of 10 nM outperformed other ROCKi, requiring significantly 1000-fold lower effective concentration than established ROCKi Y-27632 and Fasudil. Altogether, this study underscores the potential of repurposing ROCKi for treating corneal endothelial dysfunctions, offering a viable alternative to conventional grafting methods, and highlights Chroman-1 as a promising candidate structure for hit-to-lead development.

100 Deals associated with ROCKi/PKCi

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Phase 2	US	Aerie Pharmaceuticals, Inc.	31 Jan 2022
Wet age-related macular degeneration	Phase 2	US	Aerie Pharmaceuticals, Inc.	31 Jan 2022

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