The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 12, 2018
REVIEW ARTICLE

Perspective of Future Potent Therapies for Fuchs Endothelial Corneal Dystrophy



Naoki Okumura, Ryousuke Hayashi, Noriko Koizumi*
Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan

Abstract

Background:

Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive disease that affects the corneal endothelium in both eyes. Recent studies have identified a novel genetic basis for FECD, and basic research findings have provided evidence for its underlying pathophysiology. Since its first description by Ernst Fuchs in 1910, the only therapeutic choice has been corneal transplantation using donor corneas. However, accumulating evidence suggests that a change in this “rule” may be imminent.

Conclusions:

This article reviews the current knowledge of the genetics and pathophysiology of FECD, and it introduces some potent therapeutic modalities that show promise as new treatments for this disorder.

Keywords: FECD, ECM, Endothelial Corneal Dystrophy, TCF4, SNP, ICD3.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
Issue: Suppl-1, M4
First Page: 154
Last Page: 163
Publisher Id: TOOPHTJ-12-154
DOI: 10.2174/1874364101812010154

Article History:

Received Date: 12/09/2017
Revision Received Date: 16/12/2018
Acceptance Date: 30/01/2018
Electronic publication date: 23/07/2018
Collection year: 2018

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© 2018 Okumura et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tatara Miyokodani, Kyotanabe Kyoto, Japan, Tel: +81-774-65-6125; E-mail: nkoizumi@mail.doshisha.ac.jp




1. INTRODUCTION

Fuchs Endothelial Corneal Dystrophy (FECD) is a progressive disease that affects the corneal endothelium in both eyes. The hallmarks of FECD in the clinical setting are the formation of excrescences, called guttae, on Descemet’s membrane and the loss of corneal endothelial cells. FECD shows a gender dichotomy, with a female to male ratio of 2.5:1 to 3:1. FECD typically occurs at the age of 40–50, and it progresses to an advanced stage in some, but not all, patients. In the advanced stage, decompensation of the corneal epithelium disrupts the water balance in the corneal stroma, which induces edema of the corneal stroma and epithelium and causes severe vision loss [1Weisenthal R, Streeten B. Descemet’s Membrane and Endothelial Dystrophies Cornea 3rd edition. 2011;1:845-64.]. Even in patients without corneal edema, the formation of guttae and the thickening of the Descemet’s membrane due to accumulation of Extracellular Matrix (ECM) components results in forward light scatter and a loss of vision quality [2Wacker K, McLaren JW, Amin SR, Baratz KH, Patel SV. Corneal high-order aberrations and backscatter in fuchs’ endothelial corneal dystrophy. Ophthalmology 2015; 122(8): 1645-52.[http://dx.doi.org/10.1016/j.ophtha.2015.05.005] [PMID: 26050543] , 3Watanabe S, Oie Y, Fujimoto H, et al. Relationship between corneal guttae and quality of vision in patients with mild fuchs’ endothelial corneal dystrophy. Ophthalmology 2015; 122(10): 2103-9.[http://dx.doi.org/10.1016/j.ophtha.2015.06.019] [PMID: 26189189] ].

Recent studies have indicated an association between a novel genetic pattern and the development of FECD. In addition, basic research studies are now beginning to reveal the underlying pathophysiology of this disease. Despite these advances in understanding the nature of FECD, the only therapeutic choice for its treatment remains corneal transplantation using donor corneas-the original treatment used when Ernst Fuchs first described this disease in 1910 [1Weisenthal R, Streeten B. Descemet’s Membrane and Endothelial Dystrophies Cornea 3rd edition. 2011;1:845-64.]. However, accumulating evidence now indicates that important changes are imminent regarding the treatment of FECD. This article provides a review of the current knowledge of the genetics and pathophysiology of FECD, and it introduces some potent therapeutic modalities that show promise as new treatments for FECD.

2. METHODS

Literature searches were performed in PubMed (https:// www.ncbi.nlm.nih.gov/ pubmed) and ClinicalTrials.gov (https://clinicaltrials.gov/). Key search terms were the references cited in each eligible article that included “Fuchs endothelial corneal dystrophy,” “TCF4,” “single nucleotide polymorphism, SNPs, or polymorphism.” This review is not a meta-analysis; therefore, we selected literature that allowed us to introduce future perspectives as well as to summarize the current status of this research topic.

3. GENETICS

Studies of familial FECD cases show that the disease has an autosomal dominant inheritance pattern [4Eghrari AO, Riazuddin SA, Gottsch JD. Fuchs corneal dystrophy. Prog Mol Biol Transl Sci 2015; 134: 79-97.[http://dx.doi.org/10.1016/bs.pmbts.2015.04.005] [PMID: 26310151] ]. However, a certain proportion of patients with FECD have sporadic disease, without a familial history. The ICD3 classification categorizes FECD patients as those with: 1) early-onset FECD, 2) identified genetic loci, and 3) disease without known inheritance [5Weiss JS, Moller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies-edition 2. Cornea. 2015; 34(2): 117-59.].

Early-onset FECD is a rare form, and these patients exhibit corneal edema by the age of 30–40. Genetic screening of a family with early-onset FECD identified a missense mutation of the COL8A2 gene that resulted in substitution of a lysine for a glutamine (Q455K) on chromosome 1 p34.3-p32. Analysis of large families with a common form of late-onset FECD also showed a significant linkage between the FCD1, FCD2, FCD3, and FCD4 loci on chromosomes 13, 18, 5, and 9, respectively [6Sundin OH, Jun AS, Broman KW, et al. Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest Ophthalmol Vis Sci 2006; 47(1): 140-5.[http://dx.doi.org/10.1167/iovs.05-0578] [PMID: 16384955] -9Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet 2010; 86(1): 45-53.[http://dx.doi.org/10.1016/j.ajhg.2009.12.001] [PMID: 20036349] ]. Four genes (SLCA411, TCF8, LOXHD1, and AGBL1) were reported as causal genetic mutations, although these genetic mutations were rarely identified in patients with FECD [9Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet 2010; 86(1): 45-53.[http://dx.doi.org/10.1016/j.ajhg.2009.12.001] [PMID: 20036349] -14Riazuddin SA, Vasanth S, Katsanis N, Gottsch JD. Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am J Hum Genet 2013; 93(4): 758-64.[http://dx.doi.org/10.1016/j.ajhg.2013.08.010] [PMID: 24094747] ].

Researchers have since devoted their efforts to identify a genetic cause for the large proportion of patients with FECD. For example, a Genome-Wide Association Study (GWAS), conducted by Baratz and colleagues in 2010, identified a significant association between late-onset FECD and the intronic Single Nucleotide Polymorphism (SNPs) rs613872 in Transcription Factor 4 (TCF4) [15Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med 2010; 363(11): 1016-24.[http://dx.doi.org/10.1056/NEJMoa1007064] [PMID: 20825314] ]. Similarly, replication studies have shown a strong association between rs613872 and FECD, mainly in Caucasian cohorts [16Li YJ, Minear MA, Rimmler J, et al. Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. PLoS One 2011; 6(4): e18044.[http://dx.doi.org/10.1371/journal.pone.0018044] [PMID: 21533127] , 17Ołdak M, Ruszkowska E, Udziela M, et al. Fuchs endothelial corneal dystrophy: Strong association with rs613872 not paralleled by changes in corneal endothelial TCF4 mRNA level. BioMed Res Int 2015; 2015: 640234.[http://dx.doi.org/10.1155/2015/640234] [PMID: 26451375] ]. Other SNPs in TCF4, apart from rs613872, were associated with FECD in populations from Singapore, Southern China, and India, suggesting the occurrence of ethnic variations in the SNPs in TCF4 [18Thalamuthu A, Khor CC, Venkataraman D, et al. Association of TCF4 gene polymorphisms with Fuchs’ corneal dystrophy in the Chinese. Invest Ophthalmol Vis Sci 2011; 52(8): 5573-8.[http://dx.doi.org/10.1167/iovs.11-7568] [PMID: 21659310] -20Nanda GG, Padhy B, Samal S, Das S, Alone DP. Genetic association of TCF4 intronic polymorphisms, CTG18.1 and rs17089887, with Fuchs’ endothelial corneal dystrophy in an Indian population. Invest Ophthalmol Vis Sci 2014; 55(11): 7674-80.[http://dx.doi.org/10.1167/iovs.14-15297] [PMID: 25342617] ].

In 2012, Wieben and colleagues reported the discovery of an expanded CTG trinucleotide repeat in intron 3 of TCF4 in patients with FECD [21Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS One 2012; 7(11): e49083.[http://dx.doi.org/10.1371/journal.pone.0049083] [PMID: 23185296] ]. Their investigation of 66 FECD cases and 63 unaffected controls demonstrated a sensitivity and specificity of 79% and 96%, respectively, for more than 50 repeats identifying FECD; this specificity was higher than that previously reported for the rs613872 SNP. The percentages of patients with FECD that harbored the CTG trinucleotide repeat expansion varied with their ethnicities; however, this strong association was replicated in multiple ethnic groups (Table 1) [20Nanda GG, Padhy B, Samal S, Das S, Alone DP. Genetic association of TCF4 intronic polymorphisms, CTG18.1 and rs17089887, with Fuchs’ endothelial corneal dystrophy in an Indian population. Invest Ophthalmol Vis Sci 2014; 55(11): 7674-80.[http://dx.doi.org/10.1167/iovs.14-15297] [PMID: 25342617] , 22Mootha VV, Gong X, Ku HC, Xing C. Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs’ endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2014; 55(1): 33-42.[http://dx.doi.org/10.1167/iovs.13-12611] [PMID: 24255041] -27Kuot A, Hewitt AW, Snibson GR, et al. TGC repeat expansion in the TCF4 gene increases the risk of Fuchs’ endothelial corneal dystrophy in Australian cases. PLoS One 2017; 12(8): e0183719.[http://dx.doi.org/10.1371/journal.pone.0183719] [PMID: 28832669] ].

Table 1
Summary of previous reports of CTG trinucleotide repeat expansion in TCF4.


4. PATHOPHISIOLOGY

4.1. The Unfolded Protein Response

Under normal conditions, proteins undergo folding in the lumen of the Endoplasmic Reticulum (ER), and correctly folded proteins are then packaged into ER exit vesicles for delivery to membranes for extracellular secretion. By contrast, improperly folded proteins are removed in the proteasome through the process known as ER-Associated Degradation (ERAD) [28Hurtley SM, Bole DG, Hoover-Litty H, Helenius A, Copeland CS. Interactions of misfolded influenza virus hemagglutinin with Binding Protein (BiP). J Cell Biol 1989; 108(6): 2117-26.[http://dx.doi.org/10.1083/jcb.108.6.2117] [PMID: 2738090] -30Smith MH, Ploegh HL, Weissman JS. Road to ruin: Targeting proteins for degradation in the endoplasmic reticulum. Science 2011; 334(6059): 1086-90.[http://dx.doi.org/10.1126/science.1209235] [PMID: 22116878] ]. However, impairment of homeostasis induces ER stress, which disrupts ERAD and triggers apoptosis to remove rogue cells that accumulate unfolded proteins [31Walter P, Ron D. The unfolded protein response: From stress pathway to homeostatic regulation. Science 2011; 334(6059): 1081-6.[http://dx.doi.org/10.1126/science.1209038] [PMID: 22116877] , 32Rainbolt TK, Saunders JM, Wiseman RL. Stress-responsive regulation of mitochondria through the ER unfolded protein response. Trends Endocrinol Metab 2014; 25(10): 528-37.[http://dx.doi.org/10.1016/j.tem.2014.06.007] [PMID: 25048297] ]. This highly regulated process is called the Unfolded Protein Response (UPR), and the UPR is involved in the pathogenesis of various diseases, including Alzheimer’s disease, Parkinson’s disease, diabetes mellitus, multiple myeloma, and retinitis pigmentosa [33Lin JH, Lavail MM. Misfolded proteins and retinal dystrophies. Adv Exp Med Biol 2010; 664: 115-21.[http://dx.doi.org/10.1007/978-1-4419-1399-9_14] [PMID: 20238009] -38Jiang D, Niwa M, Koong AC. Targeting the IRE1α-XBP1 branch of the unfolded protein response in human diseases. Semin Cancer Biol 2015; 33: 48-56.[http://dx.doi.org/10.1016/j.semcancer.2015.04.010] [PMID: 25986851] ].

In 2010, Engler and colleagues postulated that activation of the UPR plays a central role in the pathogenesis of FECD through the induction of apoptosis in corneal endothelial cells [39Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: A unifying pathogenic pathway? Am J Ophthalmol. 2010;149(2):194-202 e2.[http://dx.doi.org/10.1016/j.ajo.2009.09.009] ]. They showed an increased and dilated ER structure and upregulation of the markers of the UPR in the corneal endothelium of patients with FECD [39Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: A unifying pathogenic pathway? Am J Ophthalmol. 2010;149(2):194-202 e2.[http://dx.doi.org/10.1016/j.ajo.2009.09.009] ]. The same research group subsequently showed that homozygous knock-in of Col8a2Q455K/Q455K, a causal gene for early-onset FECD, was sufficient to induce FECD-like ocular features in mice, and these changes were linked with UPR-associated apoptosis [40Jun AS, Meng H, Ramanan N, et al. An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis. Hum Mol Genet 2012; 21(2): 384-93.[http://dx.doi.org/10.1093/hmg/ddr473] [PMID: 22002996] ]. Recently, our group showed that ECM components, such as type I collagen and fibronectin, form aggregates of unfolded proteins in the corneal endothelium of FECD patients [41Okumura N, Kitahara M, Okuda H, et al. Sustained activation of the unfolded protein response induces cell death in fuchs’ endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2017; 58(9): 3697-707.[http://dx.doi.org/10.1167/iovs.16-21023] [PMID: 28727885] ]. We also showed that activation of transforming growth factor-β (TGF-β) signaling causes a chronic overload of ECM proteins within the ER, which induces an accumulation of unfolded protein and activation of the intrinsic apoptotic pathway through the UPR [42Okumura N, Hashimoto K, Kitahara M, et al. Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy. Sci Rep 2017; 7(1): 6801.[http://dx.doi.org/10.1038/s41598-017-06924-3] [PMID: 28754918] ]. The genetic background underlying the UPR induction is not yet elucidated; however, accumulating evidence supports a role for the UPR and associated apoptosis in FECD.

4.2. Oxidative Stress and Mitochondrial Dysfunction

Much research has confirmed an involvement of oxidative stress in the pathogenesis of FECD, and a linkage between mitochondrial dysfunction and the generation of oxidative stress is suggested [43Jurkunas UV, Rawe I, Bitar MS, et al. Decreased expression of peroxiredoxins in Fuchs’ endothelial dystrophy. Invest Ophthalmol Vis Sci 2008; 49(7): 2956-63.[http://dx.doi.org/10.1167/iovs.07-1529] [PMID: 18378575] -47Ziaei A, Schmedt T, Chen Y, Jurkunas UV. Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: A novel treatment. Invest Ophthalmol Vis Sci 2013; 54(10): 6724-34.[http://dx.doi.org/10.1167/iovs.13-12699] [PMID: 24030461] ]. For instance, an early study indicated that the numbers of mitochondria were decreased in parallel with downregulation of cytochrome oxidase [48Tuberville AW, Wood TO, McLaughlin BJ. Cytochrome oxidase activity of Fuchs’ endothelial dystrophy. Curr Eye Res 1986; 5(12): 939-47.[http://dx.doi.org/10.3109/02713688608995175] [PMID: 3026733] ]. Serial analysis of gene expression revealed that expression of mitochondrial antioxidant genes was diminished in the corneal endothelium of patients with FECD [49Gottsch JD, Bowers AL, Margulies EH, et al. Serial analysis of gene expression in the corneal endothelium of Fuchs’ dystrophy. Invest Ophthalmol Vis Sci 2003; 44(2): 594-9.[http://dx.doi.org/10.1167/iovs.02-0300] [PMID: 12556388] ]. Jurkunas and colleagues demonstrated that an oxidant-antioxidant imbalance leads to oxidative DNA damage and apoptosis [44Jurkunas UV, Bitar MS, Funaki T, Azizi B. Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. Am J Pathol 2010; 177(5): 2278-89.[http://dx.doi.org/10.2353/ajpath.2010.100279] [PMID: 20847286] ]. Very recently, Benischke and colleagues reported that constitutive activation of mitophagy causes a reduction in mitochondrial mass and depletion of the numbers of functional mitochondria [50Benischke AS, Vasanth S, Miyai T, et al. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci Rep 2017; 7(1): 6656.[http://dx.doi.org/10.1038/s41598-017-06523-2] [PMID: 28751712] ]. Accumulating evidence suggests that oxidative stress, induced by mitochondrial dysfunction, damages corneal endothelial cells. Interestingly, ER stress activates the intrinsic apoptotic pathway (the mitochondrial pathway) in the corneal endothelium, as it does in other cell types [41Okumura N, Kitahara M, Okuda H, et al. Sustained activation of the unfolded protein response induces cell death in fuchs’ endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2017; 58(9): 3697-707.[http://dx.doi.org/10.1167/iovs.16-21023] [PMID: 28727885] ]. Future studies will likely elucidate the nature of the involvement of both ER stress and oxidative stress in the pathogenesis of FECD.

4.3. RNA Foci

In 2015, Du and colleagues reported that the corneal endothelial cells of patients with FECD harbor poly(CUG)nRNA, and this results in the formation of RNA foci. They also suggested that RNA toxicity and missplicing play an important role in the pathogenesis of FECD, similar to that played in myotonic dystrophy type 1, a trinucleotide repeat expansion disease [51Du J, Aleff RA, Soragni E, et al. RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy. J Biol Chem 2015; 290(10): 5979-90.[http://dx.doi.org/10.1074/jbc.M114.621607] [PMID: 25593321] ]. Mootha and colleagues also identified RNA foci in the corneal endothelium of subjects with FECD who showed trinucleotide repeat expansion in TCF4, but these foci were absent from the corneal endothelium of subjects with FECD but without this trinucleotide repeat expansion [52Mootha VV, Hussain I, Cunnusamy K, et al. TCF4 Triplet repeat expansion and nuclear RNA foci in fuchs’ endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2015; 56(3): 2003-11.[http://dx.doi.org/10.1167/iovs.14-16222] [PMID: 25722209] ].

5. FUTURE TREATMENTS

5.1. Current Therapy

Corneal transplantation using donor corneas is currently the only therapy for treating corneal endothelial decompensation diseases, including FECD. Penetrating keratoplasty, in which a full-thickness patient cornea is replaced with full-thickness donor cornea, has been performed since 1906. New surgical procedures, such as Descemet’s Stripping Endothelial Keratoplasty (DSEK) and Descemet’s Membrane Endothelial Keratoplasty (DMEK), selectively replace the diseased corneal endothelial layer with a lamellar donor graft that includes the corneal endothelium. These lamellar surgeries have advantages over penetrating keratoplasty, and their use has therefore spread explosively [53Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet 2012; 379(9827): 1749-61.[http://dx.doi.org/10.1016/S0140-6736(12)60437-1] [PMID: 22559901] ].

5.2. Tissue Engineering Therapy

The evolution of corneal transplantation procedures now enables less invasive treatment with better clinical outcomes, but problems remain. The most serious are the shortage of donor corneas, the difficulty of the surgical procedure, and the incidence of graft failure in acute and chronic phases. These issues have motivated researchers to devise tissue engineering treatments that can overcome the current transplantation limitations [53Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet 2012; 379(9827): 1749-61.[http://dx.doi.org/10.1016/S0140-6736(12)60437-1] [PMID: 22559901] , 54Patel SV. Graft survival and endothelial outcomes in the new era of endothelial keratoplasty. Exp Eye Res 2012; 95(1): 40-7.[http://dx.doi.org/10.1016/j.exer.2011.05.013] [PMID: 21689649] ].

Two strategies adopt the use of transplanted cultured corneal endothelial cells as regenerative medicine: 1) transplantation of a cultured corneal endothelial sheet by a procedure resembling DSEK or DMEK and 2) direct injection of cultured corneal endothelial cells, without a carrier, into the anterior chamber [55Okumura N, Kinoshita S, Koizumi N. Cell-based approach for treatment of corneal endothelial dysfunction. Cornea 2014; 33(Suppl. 11): S37-41.[http://dx.doi.org/10.1097/ICO.0000000000000229] [PMID: 25188790] ]. The sheets used in transplantation are produced by culturing corneal endothelial cells on a number of different substrates, such as collagen, amniotic membrane, and human corneal stroma, and animal experiments have confirmed that the transplantation of the resulting sheet enables the regeneration of a transparent cornea [56Ishino Y, Sano Y, Nakamura T, et al. Amniotic membrane as a carrier for cultivated human corneal endothelial cell transplantation. Invest Ophthalmol Vis Sci 2004; 45(3): 800-6.[http://dx.doi.org/10.1167/iovs.03-0016] [PMID: 14985293] -59Koizumi N, Okumura N, Kinoshita S. Development of new therapeutic modalities for corneal endothelial disease focused on the proliferation of corneal endothelial cells using animal models. Exp Eye Res 2012; 95(1): 60-7.[http://dx.doi.org/10.1016/j.exer.2011.10.014] [PMID: 22067130] ]. However, to the best of our knowledge, the transplantation of cultivated corneal endothelial sheets has not yet been introduced into the clinical setting.

Some research groups, including ours, have attempted to regenerate corneal endothelium directly by injecting cultured corneal endothelial cells into the anterior chamber without a carrier [60Mimura T, Shimomura N, Usui T, et al. Magnetic attraction of iron-endocytosed corneal endothelial cells to Descemet’s membrane. Exp Eye Res 2003; 76(6): 745-51.[http://dx.doi.org/10.1016/S0014-4835(03)00057-5] [PMID: 12742357] -62Mimura T, Yamagami S, Yokoo S, et al. Sphere therapy for corneal endothelium deficiency in a rabbit model. Invest Ophthalmol Vis Sci 2005; 46(9): 3128-35.[http://dx.doi.org/10.1167/iovs.05-0251] [PMID: 16123411] ]. However, animal experiments have revealed that an insufficient number of the injected cells adhere to the back side of the cornea, so that a corneal endothelium fails to regenerate in vivo. Our previous research indicated that cell adhesion is inhibited by the activation of Rho/ROCK signaling, and conversely, inhibition of this signaling pathway by a Rho kinase (ROCK) inhibitor enhances cell adhesion. Therefore, we applied a ROCK inhibitor to promote engraftment [63Okumura N, Ueno M, Koizumi N, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci 2009; 50(8): 3680-7.[http://dx.doi.org/10.1167/iovs.08-2634] [PMID: 19387080] , 64Okumura N, Sakamoto Y, Fujii K, et al. Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. Sci Rep 2016; 6: 26113.[http://dx.doi.org/10.1038/srep26113] [PMID: 27189516] ]. We confirmed, using rabbit and monkey corneal endothelial dysfunction models, that coinjection of cultured corneal endothelial cells and a ROCK inhibitor into anterior chamber resulted in the regeneration of the corneal endothelium [64Okumura N, Sakamoto Y, Fujii K, et al. Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. Sci Rep 2016; 6: 26113.[http://dx.doi.org/10.1038/srep26113] [PMID: 27189516] , 65Okumura N, Koizumi N, Ueno M, et al. ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol 2012; 181(1): 268-77.[http://dx.doi.org/10.1016/j.ajpath.2012.03.033] [PMID: 22704232] ].

In 2013, after obtaining the approval from the Japanese Ministry of Health, Labour, and Welfare, we initiated a clinical trial (Clinical trial registration: UMIN000012534) at the Kyoto Prefectural University of Medicine to evaluate this cell injection therapy as a treatment for corneal endothelial dysfunction [66Okumura N, Kinoshita S, Koizumi N. Application of Rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol 2017; 2017: 2646904.[http://dx.doi.org/10.1155/2017/2646904] [PMID: 28751979] ]. Our preliminary clinical data have confirmed that coinjection of cultured corneal endothelial cells and a ROCK inhibitor regenerates the corneal endothelium and restores a transparent cornea in human subjects. Further clinical data are necessary, but cell-based therapy appears to be a potent future treatment for corneal endothelial decompensation diseases, including FECD.

5.3. ROCK Inhibitor Eye Drops

Rho is a small GTPase, and RhoA activates ROCK, a serine/threonine kinase that phosphorylates various substrates. ROCK signaling plays an essential role in several fundamental cellular events, such as cell adhesion, motility, proliferation, differentiation, and apoptosis [67Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996; 392(2): 189-93.[http://dx.doi.org/10.1016/0014-5793(96)00811-3] [PMID: 8772201] -69Narumiya S, Tanji M, Ishizaki T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 2009; 28(1-2): 65-76.[http://dx.doi.org/10.1007/s10555-008-9170-7] [PMID: 19160018] ]. In 2009, we reported that inhibition of ROCK signaling promotes the in vitro proliferation of corneal endothelial cells [63Okumura N, Ueno M, Koizumi N, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci 2009; 50(8): 3680-7.[http://dx.doi.org/10.1167/iovs.08-2634] [PMID: 19387080] ]. Subsequently, we found that administration of a ROCK inhibitor in eye drop form promotes wound healing in the corneal endothelium in rabbit and monkey models [70Okumura N, Koizumi N, Ueno M, et al. Enhancement of corneal endothelium wound healing by Rho-associated Kinase (ROCK) inhibitor eye drops. Br J Ophthalmol 2011; 95(7): 1006-9.[http://dx.doi.org/10.1136/bjo.2010.194571] [PMID: 21398412] -72Okumura N, Inoue R, Okazaki Y, et al. Effect of the Rho kinase inhibitor y-27632 on corneal endothelial wound healing. Invest Ophthalmol Vis Sci 2015; 56(10): 6067-74.[http://dx.doi.org/10.1167/iovs.15-17595] [PMID: 26393474] ].

We have since conducted pilot clinical research to investigate the use of topically applied ROCK inhibitor eye drops in patients who have undergone central corneal endothelium removal by transcorneal freezing. Our findings suggested that the eye drop form of ROCK inhibitor is a potent therapeutic treatment choice for patients with early-stage FECD [71Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci 2013; 54(4): 2493-502.[http://dx.doi.org/10.1167/iovs.12-11320] [PMID: 23462749] , 73Koizumi N, Okumura N, Ueno M, Nakagawa H, Hamuro J, Kinoshita S. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea 2013; 32(8): 1167-70.[http://dx.doi.org/10.1097/ICO.0b013e318285475d] [PMID: 23715376] ]. Notably, one 52-year-old male patient diagnosed with late-onset FECD recovered full corneal transparency after transcorneal freezing and the use of ROCK inhibitor eye drops. His central corneal thickness was reduced from 703 μm to 568 μm and his visual acuity improved from 20/63 to 20/20. His corneal transparency was maintained for more than 6 years, and the original plans for an eventual corneal transplantation were canceled [73Koizumi N, Okumura N, Ueno M, Nakagawa H, Hamuro J, Kinoshita S. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea 2013; 32(8): 1167-70.[http://dx.doi.org/10.1097/ICO.0b013e318285475d] [PMID: 23715376] ].

Recent investigations have examined the effect of surgical removal of the central Descemet’s membrane, including pathological corneal endothelium [74Shah RD, Randleman JB, Grossniklaus HE. Spontaneous corneal clearing after Descemet’s stripping without endothelial replacement. Ophthalmology 2012; 119(2): 256-60.[http://dx.doi.org/10.1016/j.ophtha.2011.07.032] [PMID: 21982414] -76Bleyen I, Saelens IE, van Dooren BT, van Rij G. Spontaneous corneal clearing after Descemet’s stripping. Ophthalmology 2013; 120(1): 215.[http://dx.doi.org/10.1016/j.ophtha.2012.08.037] [PMID: 23283191] ], and one clinical study has indicated a positive effect of combining ROCK inhibitor eye drops with this procedure [77Moloney G, Petsoglou C, Ball M, et al. Descemetorhexis without grafting for fuchs endothelial dystrophy-supplementation with topical ripasudil. Cornea 2017; 36(6): 642-8.[http://dx.doi.org/10.1097/ICO.0000000000001209] [PMID: 28476048] ]. However, clinical data for the usefulness of ROCK inhibitors in FECD treatment remain limited, so randomized clinical trials are still needed before adoption of this eye drop as a routine therapeutic option.

5.4. Potent Pharmaceutical Agents

Stealth BioTherapeutics (Newton, MA) has been developing drug candidates for targeting diseases associated with mitochondrial dysfunction. They initiated a phase 2 clinical trial of elamipretide in eye drop form, with the expectation that this drug would target the inner mitochondrial membrane to help preserve mitochondrial energetics (http://www.stealthbt.com/). The results of this clinical trial have not yet been released, but elamipretide is currently the most advanced-stage pharmaceutical aimed at the treatment of FECD.

Kim and colleagues reported that N-Acetylcysteine (NAC), a thiol-containing antioxidant and radical scavenger, rescued cultured corneal endothelial cells from damage mediated by ER and oxidative stress [78Kim EC, Meng H, Jun AS. N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. Exp Eye Res 2014; 127: 20-5.[http://dx.doi.org/10.1016/j.exer.2014.06.002] [PMID: 24952277] ]. They also demonstrated that systemic use of NAC suppressed the progression of FECD in early-onset FECD model mice (Col8a2Q455K/Q455K), thereby providing an in vivo proof of concept of the use of NAC as a potent therapeutic candidate for treatment of FECD [78Kim EC, Meng H, Jun AS. N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. Exp Eye Res 2014; 127: 20-5.[http://dx.doi.org/10.1016/j.exer.2014.06.002] [PMID: 24952277] ]. The same research group also showed that the addition of lithium further increased the survival of cultured corneal endothelial cells when ER and oxidative stresses were triggered [79Kim EC, Meng H, Jun AS. Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br J Ophthalmol 2013; 97(8): 1068-73.[http://dx.doi.org/10.1136/bjophthalmol-2012-302881] [PMID: 23759441] ]. A higher corneal endothelial cell density was also maintained in early-onset FECD model mice given a lithium treatment than in a non-treatment group [79Kim EC, Meng H, Jun AS. Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br J Ophthalmol 2013; 97(8): 1068-73.[http://dx.doi.org/10.1136/bjophthalmol-2012-302881] [PMID: 23759441] ]. The researchers suggested that lithium increases the survival of corneal endothelial cells by an upregulation of autophagy; therefore, lithium may represent a new therapeutic agent for the treatment of FECD [79Kim EC, Meng H, Jun AS. Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br J Ophthalmol 2013; 97(8): 1068-73.[http://dx.doi.org/10.1136/bjophthalmol-2012-302881] [PMID: 23759441] ].

More recently, the same group attempted a drug screening based on the postulated FECD pathophysiology involving ER and oxidative stresses and cell death [80Kim EC, Toyono T, Berlinicke CA, et al. Screening and characterization of drugs that protect corneal endothelial cells against unfolded protein response and oxidative stress. Invest Ophthalmol Vis Sci 2017; 58(2): 892-900.[http://dx.doi.org/10.1167/iovs.16-20147] [PMID: 28159976] ]. They induced ER stress with thapsigargin and oxidative stress with hydrogen peroxide in cultured corneal endothelial cells, and then screened 640 compounds found in the Food and Drug Administration (FDA)-approved drug library. They reported that oxotremorine and mefenamic acid were potential survival factors that overcame stress-related cell death.

Our group has reported that activation of TGF-β signaling activates genes that induce the epithelial-mesenchymal transition (EMT). These include ZEB1 and SNAI1, and their induction results in the accumulation of ECM components [81Okumura N, Minamiyama R, Ho LT, et al. Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy. Lab Invest 2015; 95(11): 1291-304.[http://dx.doi.org/10.1038/labinvest.2015.111] [PMID: 26302187] ]. This production of ECM components was more strongly upregulated in cell models established from patients with FECD than in control corneal endothelial cells, following exposure of the cells to TGF-β. We recently reported high expression levels of TGF-β isoforms and TGF-β receptors in the corneal endothelium of patients with FECD, and we proposed that activation of TGF-β signaling induces a chronic overload of ECM components, resulting in apoptosis through the UPR [42Okumura N, Hashimoto K, Kitahara M, et al. Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy. Sci Rep 2017; 7(1): 6801.[http://dx.doi.org/10.1038/s41598-017-06924-3] [PMID: 28754918] ]. We also showed that inhibition of TGF-β signaling suppressed this accumulation of ECM components and suppressed UPR-mediated apoptosis in cell models established from patients with FECD. These findings suggest that inhibition of TGF-β might be a potent therapeutic option [42Okumura N, Hashimoto K, Kitahara M, et al. Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy. Sci Rep 2017; 7(1): 6801.[http://dx.doi.org/10.1038/s41598-017-06924-3] [PMID: 28754918] ]. A summary of the proposed drug candidates for treating FECD is shown in Table 2.

Table 2
Proposed drug candidates for treating FECD.


CONCLUSION

Corneal transplantation has been the only therapy available for treating FECD for many years. However, recent advancements in tissue engineering techniques may now provide innovative cell-based therapies. “Missing links” still necessitate further investigations, but new information regarding the genetic background and pathophysiology of FECD is rapidly accumulating. Importantly, the recent findings improve the understanding of FECD, but they also guide further investigations aimed at identifying future therapeutic modalities. Indeed, several drug candidates have recently been reported, although none of these drugs has yet been introduced into the market. Corneal transplantations using donor corneas continue to remain the standard treatment, but we believe that the new therapeutic options, such as cell-based therapy and the use of pharmaceutical agents, will provide less invasive and more effective therapies.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

Noriko Koizumi is listed as the inventor of the patent regarding the application of the ROCK inhibitor for corneal endothelium regeneration (registration number: 5657252). Noriko Koizumi and Naoki Okumura are listed as inventors of the patent regarding the application of TGF-β signal inhibition for treatment of Fuchs endothelial corneal dystrophy.

ACKNOWLEDGEMENT

This study was supported by the Program for the Strategic Research Foundation at Private Universities from MEXT (Koizumi, N. and Okumura, N.), JSPS KAKENHI Grant Numbers JP16K11307 (Koizumi, N) and JP 15K10885 (Okumura, N.).

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