Coneapatient
Coneapatient
Coneapatient
healing of the corneal endothelium in vivo.3 Here, we present per square millimeter. The left cornea showed severe central edema
a case of Fuchs corneal dystrophy scheduled for DSAEK accompanied by epithelial bullae (Figs. 2A, B). The central corneal
surgery but successfully treated by ROCK inhibitor eye drop thickness was 703 mm in the affected left eye of the patient. We were
treatment subsequent to transcorneal freezing. unable to perform specular microscopy in the central cornea owing
to the edema, but endothelial cells were observed in the midperiph-
ery at a density of 757 cells per square millimeter (Fig. 1B). The
patient was diagnosed with late-onset Fuchs corneal dystrophy.4 He
CASE REPORT was scheduled to have a DSAEK, but in April 2010, he volunteered
A 52-year-old Japanese man with blurred vision caused by for an investigative clinical study of a ROCK inhibitor eye drop
corneal endothelial dysfunction was referred to the Kyoto Prefectural treatment.
University of Medicine in May 2008. Visual acuity was 20/20 in the Treatment was initiated on May 18, 2010, according to
right eye and 20/63 in the left eye. Multiple guttae, typical of Fuchs a protocol approved by the Institutional Review Board of the Kyoto
corneal dystrophy, were observed in both eyes by slit-lamp Prefectural University of Medicine. First, diseased corneal endothe-
examination and by noncontact specular microscopy (EM-3000; lium in the prepupillary region was removed by transcorneal
TOMEY Corporation, Nagoya, Japan) (Figs. 1A, B). The right cor- freezing3 by gently pressing a 2-mm-diameter stainless steel rod,
nea was clear, although the corneal endothelial density was 632 cells which had been cooled in liquid nitrogen onto the corneal surface
for 15 seconds. In our previous study using a rabbit model, we whose proliferation had been stopped by contact inhibition.
confirmed that this transcorneal freezing procedure could make an Based on this, and on the results of experiments in rabbits,3 we
endothelial defect of approximately the same size as the rod diameter hypothesized that the topical application of Y-27632 as an eye
in a reproducible fashion.3 After the rod was removed and after the drop, combined with the prior partial denudation of diseased
cornea had thawed, 50 mL of 10 mM ROCK inhibitor, Y-27632
corneal endothelial cells, might be useful to promote the pro-
(Wako, Osaka, Japan), was applied topically as eye drops, repeated
6 times daily for 7 days (May 18–24, 2010). To prevent corneal liferation in situ of the corneal endothelium, which is in the early
infection, 0.3% gatifloxacin hydrate eye drops were also applied diseased phase. Thus, we came up with the protocol reported
4 times daily. Epithelial erosion was detected after transcorneal here, which shows some potential for the new approach to treat
freezing but had healed by posttreatment day 3 (Figs. 2C, D). No certain types of corneal endothelial dysfunction.
side effects, such as persistent epithelial defects or corneal stromal In the posttreatment observation of the presented case,
scars, were observed. contact specular microscopy revealed relatively small corneal
The patient’s cornea recovered complete clarity 2 weeks after endothelial cells, present at a high cell density, in the central
the treatment, and vision had improved to 20/20. Six months after part of cornea from where corneal endothelial cells had been
the treatment, central corneal thickness was 568 mm, significantly removed by transcorneal freezing. The potential of topical
lower than its pretreatment value. At this time, vision had improved
application of ROCK inhibitor suggested by the current report
to 20/16 (Figs. 2E, F). Wide-field endothelial examinations 18
months after the treatment using contact specular microscopy clearly requires a larger comparative study to prove the effect
(Konan Medical, Inc, Nishinomiya, Japan; Fig. 3A) showed that of this new treatment, and plans are underway to conduct this.
the average corneal endothelial densities in the central and peripheral Regarding the mechanism of action of the procedure, we
cornea were 1549.3 6 89.7 and 705 6 61.1 cells per square milli- should also point out that spontaneous remodeling of the
meter, respectively (mean 6 standard error of the mean; Fig. 3B). human corneal endothelial cells after Descemet stripping has
Although Fuchs corneal dystrophy is a progressive disease, in our been reported.9,10 Based on these reports, and also bearing
patient, corneal clarity and good vision (20/16) have been main- in mind the existence of corneal endothelial precursors with
tained up to the most recent observation, 2-years after the treatment higher proliferative ability in the peripheral cornea,11,12 we
(Figs. 1G, H). cannot rule out the possibility that reestablishment of this
patient’s endothelium was not a direct result of ROCK inhib-
itor administration, but it was the consequence of denudation
DISCUSSION of the pathologic endothelial cells. Not withstanding the pre-
ROCKs are protein serine/threonine kinases, which are liminary nature of the current observation, this case report
the first identified and best-characterized Rho downstream suggests the possibility of a medical treatment for the early
effectors. The Rho/ROCK pathway is involved in regulating phase of diseases, such as Fuchs corneal dystrophy, via the
the cytoskeleton and has an influence on cell migration, stimulation of nonaffected peripheral cells with ROCK inhib-
apoptosis, and proliferation.5–8 itor after the destruction of diseased cells in the central endo-
We previously reported that a selective ROCK inhibitor, thelium by transcorneal freezing.
Y-27632, promoted the proliferation of primate corneal endo- To the best of our knowledge, this is the first report
thelial cells in vitro.2 In our previous experiments, Y-27632 pro- suggesting that the in vivo proliferation of a patient’s corneal
moted cell proliferation up to the time when cells became endothelium can be stimulated by interventional medical/
preconfluent but did not promote proliferation in confluent cells pharmaceutical treatment after the destruction of diseased
endothelium. We believe that our new findings will contribute 4. Eghrari AO, Gottsch JD. Fuchs’ corneal dystrophy. Expert Rev Ophthal-
to the opening up of a new approach to the treatment of mol. 2010;5:147–159.
5. Coleman ML, Marshall CJ, Olson MF. RAS and RHO GTPases in G1-phase
corneal endothelial dysfunction. cell-cycle regulation. Nat Rev Mol Cell Biol. 2004;5:355–366.
6. Hall A. Rho GTPases and the actin cytoskeleton. Science 1998;279:
509–514.
ACKNOWLEDGMENTS 7. Olson MF, Ashworth A, Hall A. An essential role for Rho, Rac, and
The authors thank Dr. Yoshiki Sasai (RIKEN CDB, Cdc42 GTPases in cell cycle progression through G1. Science. 1995;269:
Japan) for his invaluable advice regarding ROCK inhibitors 1270–1272.
8. Watanabe K, Ueno M, Kamiya D, et al. A ROCK inhibitor permits
and Prof. Andrew Quantock (Cardiff University, United survival of dissociated human embryonic stem cells. Nat Biotechnol.
Kingdom) for useful discussions. 2007;25:681–686.
9. Balachandran C, Ham L, Verschoor CA, et al. Spontaneous corneal
clearance despite graft detachment in Descemet membrane endothelial
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