Expanding Options for Rho-Associated Protein Kinase Inhibitors

Most people are focused on finding new and better sources of protein, but what about finding something that activates protein instead? How can ophthalmology use protein to activate better patient outcomes?

The good news is that Rho inhibitors are showing a strong capability of revealing the workings of protein activation. Friedrich Kruse MD provided a comprehensive overview of the topic at a recent conference.

Dr Kruse first described Rho-associated protein kinase inhibitors (ROCKis) as serine-threonine kinases, i.e., downstream effectors of Rho-GTPase, which activate in response to growth factors such as hormones, cytokines, integrins, cell stress, and wound healing.

The ROCK 1/2 variant activates approximately 40 proteins through adenosine triphosphate (ATP)-dependent phosphorylation. According to Dr Kruse, these play a critical role in cell adhesion, migration, proliferation, contraction, and apoptosis via the modulation of the cytoskeleton.

ROCKis have enjoyed considerable utility in ophthalmology, with ripasudil and netarsudil as the most widely known. The former is a non-selective ROCK 1/2 applied as topical eye drops for glaucoma and intraocular hypertension (IOP).

Netarsudil, on the other hand, is a norepinephrine transporter (NET) ROCK 1/2 that’s also applied as an eye drop, primarily used to treat open-angle glaucoma and lower IOP.

“IOP in the patient is lowered by ROCKis via the enhancement of the trabecular meshwork and by Schlemm’s canal outflow,” Dr Kruse explained. “In experimental use, they can reduce subconjunctival fibrosis after filtration surgery and could provide neuroprotection in retinal and optic nerve ischaemia by enhancing blood flow.”

There are many possibilities when it comes to applying ROCKis in endothelial disease, including endothelial protection during surgery, corneal oedema (as an adjunct to Descemet stripping only [DSO]), corneal endothelial cell (CEC) injections, and Fuchs’ endothelial corneal dystrophy (FECD).

For example, ripasudil’s efficacy in treating FECD is considerable thanks to its ability to interact with cell matrices. Dr Kruse said the drug achieves this by causing “significant downregulation of FECD-related matrix components and concomitant upregulation of matrix metalloproteinases (MMPs).”

He also highlighted applications of ROCKis as adjuncts in DSO, describing how drugs like ripasudil and netarsudil “support endothelial wound healing and regeneration by promoting endothelial cell migration, proliferation, and healing.”

He added that clinical studies have shown that using ROCKis is associated with faster visual recovery and higher success rates than with DSO alone.

In terms of what to expect from ROCKis in the future, Dr Kruse said there’s potential for further advancements in corneal oedema treatment, as well as for graft survival enhancement after Descemet membrane endothelial keratoplasty.

“We’re now at a point where we can think about pharmacologic regeneration, helping the cornea restore itself instead of replacing it,” Dr Kruse said. “This could fundamentally change how we treat endothelial disease—with less reliance on transplants and more focus on biology.”

Dr Kruse spoke at the 2025 ESCRS Annual Congress in Copenhagen.

Friedrich E Kruse MD is Chairman of the Department of Ophthalmology at University Hospital Erlangen, Germany. friedrich.kruse@uk-erlangen.de