The ROCK Inhibitor Eye Drop Accelerates Corneal Endothelium Wound Healing

Abstract

Citation: Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci. 2013;54:243954: -250254: . DOI:10. 1167 PURPOSE. To evaluate the effect of Rho kinase (ROCK)-inhibitor eye drops on a corneal endothelial dysfunction primate model and human clinical case series of corneal endothelial dysfunction.METHODS. As a corneal-endothelial partially injured model, the corneal endothelium of seven cynomolgus monkeys was damaged by transcorneal freezing; 10 mM of ROCK inhibitor Y-27632 was then applied topically 6 times daily. The phenotype of the reconstructed corneal endothelium was evaluated by immunohistochemical analysis and noncontact specular microscopy. For clinical study, the effect of Y-27632 eye drops after transcorneal freezing was evaluated in eight corneal endothelial dysfunction patients: four central corneal edema patients and four diffuse corneal edema patients.RESULTS. Slit-lamp microscopy revealed that both Y-27632-treated and -nontreated corneas became hazy after transcorneal freezing, and then recovered their transparency within 4 weeks. ROCK inhibitor Y-27632 promoted recovery of corneal endothelial cell density and wound healing in terms of both morphology and function. The percentage of ZO-1 and Na þ / K þ -ATPase positive cells in the regenerated area in the Y-27632 group was significantly higher than in the controls. Noncontact specular microscopy revealed that corneal endothelial cell density was significantly higher in the Y-27632 group compared with the controls at 4 weeks; cell density reached approximately 3000 cells/mm 2 , as opposed to 1500 cells/mm 2 in the control group. In addition to the animal study findings, the clinical study findings showed that Y-27632 eye drops effectively improved corneal edema of corneal endothelial dysfunction patients with central edema. 2 However, several severe problems can arise associated with corneal transplantation, including allograft rejection, primary graft failure, and severe loss of cell density. To the best of our knowledge, no clinically practical medical therapy has been developed to effectively treat corneal endothelial dysfunction.As an alternative to corneal transplantation, regenerative medical procedures might be a plausible path of therapy for treating severe corneal endothelial dysfunction. Several research groups, including ours, have reported transplantations of cultivated CECs in an animal model to establish a new clinical intervention for corneal endothelial dysfunction. [3][4][5][6][7][8][9] We recently reported the use of cell therapy to successfully achieve the recovery of corneal transparency in both rabbit and primate corneal endothelial dysfunction models. 9 However, in cases of early-stage corneal endothelial dysfunction, in which stem cells or progenitor cells are still maintained in the tissue, drug therapy may provide a less-invasive or antiprogression treatment. Our group, as well as several other groups, reported that pharmaceutical agents such...

ROCK inhibitors in ocular disease

“…A phase 1 clinical trial was performed in Japan involving 10 healthy volunteers. This study confirmed that Y27632, applied as 10 mM eye drops 6 times daily for 7 days, did not cause any systemic or local side effects [30]. Eight patients who suffered from corneal deficiency were subsequently enrolled to test the feasibility of the drug in pathological conditions.…”

“…After two days the difference between the treated and the non-treated eye in the size of the wound was remarkable. Furthermore, after one week non-contact specular microscopy showed normal cell morphology and cell density (of 3000 cell/mm 2 ) in the treated group, in contrast with the control group, where the examined area exhibited enlarged corneal endothelial cells (CEC) and a cell density of only 1500 cells/mm 2 [30].…”

Clinical outcomes after Descemet’s stripping endothelial keratoplasty using donor corneas from children younger than 3 years

“…In vivo human corneal endothelial cells are thought to be arrested at the G1 phase of the cell cycle; thus, proliferation is inhibited 26. A purely medical treatment for corneal endothelial disease has been sought for quite some time, and several interesting agents have been explored for this purpose, such as EDTA,27 EGF, PDGE, FGF‐2,28 siRNA of Connexin 43,29 R‐spondin 130 and ROCK inhibitor 31. However, these agents have not yet been introduced into the clinical setting.…”

Rhokinase Inhibitors novel Potential Treatment Modality for Glaucoma

“…3. Facilitate corneal endothelium wound healing: RKI Y-27632 has been shown to increase corneal endothelial cell density and restore function in animals with partially injured cornea 23 , suggesting a role for rhokinase inhibitors as a potential therapeutic treatment for certain forms of corneal endothelial cell dysfunction in humans.…”