Application of Rho Kinase Inhibitors for the Treatment of Corneal Endothelial Diseases

Abstract

ROCK (Rho kinase) signaling regulates a wide spectrum of fundamental cellular events and is involved in a variety of pathological conditions. It has therefore attracted research interest as a potential therapeutic target for combating various diseases. We showed that inhibition of ROCK enhances cell proliferation, promotes cell adhesion onto a substrate, and suppresses apoptosis of corneal endothelial cells (CECs). In addition, we reported that a ROCK inhibitor enhances wound healing in the corneal endothelium in animal models and in pilot clinical research. We also demonstrated the usefulness of a ROCK inhibitor as an adjunct drug in tissue engineering therapy as it enhances the engraftment of CECs onto recipient corneas. In 2013, we initiated a clinical trial to test the effectiveness of injection of cultured human CECs into the anterior chamber of patients with corneal endothelial decompensation. This paper reviews the accumulating evidence supporting the potency of ROCK inhibitors in clinical use, both as eye drops and as adjunct drugs in cell-based therapies, for the treatment of corneal endothelial decompensation.

Figure 1

Future treatment strategies for corneal endothelial decompensation. Pharmaceutical treatments and tissue engineering therapies are possible innovative therapeutic modalities. Reproduced from Okumura [49].

Figure 2

Effect of Y-27632 on wound healing in a corneal endothelial damage rabbit model. (a) Half of the corneal endothelium area was mechanically scraped. Y-27632 (10 mM) diluted in phosphate-buffered saline (PBS) was applied topically 6 times daily, and PBS was applied 6 times daily as a control. Corneal transparency was assessed by slit-lamp microscopy for 14 days (n = 6). Representative anterior segment images are shown. (b, c) Anterior segments were also evaluated with a Pentacam®. Representative Scheimpflug images and corneal thickness maps obtained with the Pentacam HR are shown. Values in the corneal thickness map are indicated in μm. Reproduced from Okumura et al. [27].

Figure 3

Clinical research on the use of ROCK-inhibitor Y-27632 eye drops for treatment of corneal decompensation. A representative case of a patient with central corneal edema due to Fuchs endothelial corneal dystrophy is shown. Before treatment, central corneal edema was observed (a), but the corneal edema was eliminated and visual acuity recovered from logMAR 0.70 to −0.18 after 6 months of treatment (b). Reproduced from Okumura et al. [26].

Figure 4

Pilot clinical research on the use of ROCK inhibitor eye drops for the treatment of acute corneal endothelial damage due to cataract surgery. (a) An 84-year-old female diagnosed with cataract underwent phacoemulsification. During the surgery, the Descemet's membrane was spontaneously detached from the upper incision tunnel and over 2/3 was aspirated. The patient was referred to the cornea clinic of Kyoto Prefectural University of Medicine due to severe corneal edema. The patient was treated with the 1 mM Y-27632 eye drops for 6 months. At 2 weeks, the cornea had recovered its clarity, and the patient's visual acuity had improved to 20/20 at 3 months. (b) Panoramic image of the corneal endothelium, evaluated by contact specular microscopy after 3 months. The Descemet's removal line is indicated as a white dotted line. Reproduced from Okumura et al. [27].

Figure 5

Schematic images of the cultured corneal endothelial cell (CEC) injection therapy. (a) Coinjection of cultured CECs with a ROCK inhibitor into the anterior chamber; (b) patient in the facedown position, to allow the CECs to sink down to the anterior chamber side of the cornea; (c) maintenance of the facedown position for 3 hours; (d) regeneration of the corneal endothelium by the injected cultured CECs. Reproduced from Okumura et al. [48].

Figure 6

Representative images of the effectiveness of cultured corneal endothelial cell (CEC) injection therapy in clinical research. Representative slit-lamp microscopy images of the first patient, a Japanese female with corneal endothelial decompensation induced by argon laser iridotomy (a). After mechanical removal of an 8 mm diameter section of the corneal endothelium, cultured human CECs together with a ROCK inhibitor were injected into the anterior chamber. Preoperative visual acuity was 0.04 due to the edema in the corneal epithelium and stroma. The postoperative visual acuity recovered to 1.0, together with the associated recovery of corneal transparency (b).