Naoki Okumura

Naoki Okumura
Doshisha University · Department of Biomedical Engneering

MD., PhD.

About

99
Publications
22,711
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Introduction
I have been developing both pharmaceutical and tissue engineering treatment for corneal endothelial dysfunction. We demonstrated that the ROCK inhibitor promotes corneal endothelial cell (CECs) proliferation, and started a clinical trial of ROCK inhibitor eye drops. We also demonstrated that corneal transparency was restored via the injection of cultivated CECs into the anterior chamber in animal model. Of note, our team has started the clinical trial of cultivated CEC-injection therapy.
Additional affiliations
April 2020 - present
Doshisha University
Position
  • Professor (Full)
March 2015 - March 2020
Doshisha University
Position
  • Professor (Associate)
April 2011 - March 2015
Doshisha University
Position
  • Professor (Assistant)

Publications

Publications (99)
Article
Full-text available
The transplantation of cultivated corneal endothelial cells (CECs) has gained attention recently for the treatment of patients with corneal endothelial dysfunction. However, an efficient culturing technique for human (H)CECs has yet to be properly established. The present study was conducted to investigate the applicability of the Rho kinase (ROCK)...
Article
Corneal endothelial dysfunction accompanied by visual disturbance is a primary indication for corneal transplantation. We previously reported that the adhesion of corneal endothelial cells (CECs) to a substrate was enhanced by the selective ROCK inhibitor Y-27632. It is hypothesized that the inhibition of ROCK signaling may manipulate cell adhesion...
Article
Background: Corneal endothelial cell (CEC) disorders, such as Fuchs's endothelial corneal dystrophy, induce abnormal corneal hydration and result in corneal haziness and vision loss known as bullous keratopathy. We investigated whether injection of cultured human CECs supplemented with a rho-associated protein kinase (ROCK) inhibitor into the ante...
Article
Full-text available
Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patient...
Article
Full-text available
Purpose: To investigate single nucleotide polymorphisms (SNPs) and trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene in a large cohort of German patients with Fuchs endothelial corneal dystrophy (FECD). Methods: Genomic DNA was obtained from 398 patients with FECD and from 58 non-FECD controls. Thirty-seven previousl...
Article
Full-text available
In 2013, a clinical trial was initiated to investigate cell therapy for the treatment of corneal endothelial decompensation. Cultivating human corneal endothelial cells (CECs) while maintaining their functional phenotype is challenging; therefore, establishment of a confirmed protocol is pivotal for obtaining approval from regulatory authorities fo...
Article
Full-text available
PURPOSE To investigate the safety and efficacy of cultured human corneal endothelial cell (hCEC)-injection therapy with mature differentiated (mature) cell subpopulations (SPs) for corneal endothelial failure (CEF). DESIGN Comparative, interventional case series. METHODS This study involved 18 eyes with CEF that underwent cultured hCEC-injection...
Chapter
This work presents a numerical scheme based on operator splitting for the thermo-fluid-dynamical simulation of aqueous humor flow in the anterior chamber of the human eye. The stability properties of the scheme are investigated theoretically. Numerical results are presented for different postures and different external temperatures.
Article
Purpose: The purpose of this article was to study the clinical, optical, and morphological correlates of visual function in patients with Fuchs endothelial corneal dystrophy (FECD). Methods: The case records were analyzed for patients diagnosed with FECD between September 2019 and March 2020. The best-corrected visual acuity (BCVA) was recorded...
Conference Paper
Purpose : Patients with Fuchs endothelial corneal dystrophy (FECD) often harbor expansion of a trinucleotide CTG repeat in the TCF4 gene, thus suggesting that TCF4 is a potential causative gene for FECD. We previously reported that the expression of TCF4 is upregulated in the corneal endothelium of FECD patients. The purpose of this present study w...
Article
Purpose: The aim of this study was to investigate the immune cells on corneal endothelium of the graft in patients who underwent penetrating keratoplasty (PK), Descemet-stripping endothelial keratoplasty (DSEK), and Descemet membrane endothelial keratoplasty (DMEK). Methods: A total of 43 eyes of 43 patients who underwent PK (17 eyes), DSEK (13...
Article
Full-text available
Purpose: To report evidences that the abnormal endothelium of some Fuchs endothelial corneal dystrophy (FECD) present centripetal radial lines over 360 degrees. Methods: A case report of retroilluminated pictures of 2 patients with FECD and flat mounts of isolated Descemet membranes of 1 patient with FECD and of 1 healthy donor. Interpretation a...
Article
Purpose TGF‐βs trigger ENdothelial‐Mesenchymal Transition (EnMT) in corneal endothelial cells (ECs) in animal models of endothelial wound healing. All the 3 isoforms of TGF‐β were detected in human aqueous humor and their receptors were detected in ECs. More and more evidence indicated that central and peripheral ECs have a different status. Aim T...
Article
Purpose Rho-associated kinase (ROCK) inhibitors have been successfully used as a rescue strategy in eyes that failed to clear after descemetorhexis without endothelial graft for treatment of Fuchs endothelial corneal dystrophy (FECD). The functional mechanisms by which ROCK inhibitors modulate corneal endothelial cell regeneration in FECD patients...
Article
Full-text available
The corneal endothelium maintains corneal transparency; consequently, damage to this endothelium by a number of pathological conditions results in severe vision loss. Publicly available expression databases of human tissues are useful for investigating the pathogenesis of diseases and for developing new therapeutic modalities; however, databases fo...
Article
Full-text available
Purpose: To report the safety and efficacy of a novel cell-injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term clinical data of 5-years postoperative in a 'first-in-man' clinical trial group. Design: Prospective observational study. Participants: This study...
Article
Introduction Tissue engineering therapy for the treatment of corneal endothelial decompensation was proposed in the 1970s. In 2013, a clinical trial of the injection of cultured human corneal endothelial cells into the anterior chamber of patients with corneal endothelial decompensation was started in Japan. Areas covered The aim of this paper is...
Article
Penetrating keratoplasty was the only therapeutic choice for the treatment of corneal endothelial decompensation until the introduction of evolutional endothelial keratoplasties, namely Descemet’s stripping automated endothelial keratoplasty (DSAEK) and Descemet’s membrane endothelial keratoplasty (DMEK). Although now in widespread use, DSAEK and D...
Article
Purpose: To evaluate the association of single nucleotide polymorphisms (SNPs) and the intronic expansion of a trinucleotide repeat (TNR) in the TCF4 gene with Fuchs endothelial corneal dystrophy (FECD) in a Thai population. Methods: In total, 54 Thai FECD patients and 54 controls were recruited for the study. Five SNPs (rs613872, rs2123392, rs1...
Article
Full-text available
Transparency of the cornea is essential for vision and is maintained by the corneal endothelium. Consequently, corneal endothelial decompensation arising from irreversible damage to the corneal endothelium causes severe vision impairment. Until recently, transplantation of donor corneas was the only therapeutic choice for treatment of endothelial d...
Article
Full-text available
Purpose Hospital-prepared topical ganciclovir eye drops made from intravenous infusions are used to treat cytomegalovirus corneal endotheliitis. This study assessed the efficacy of these eye drops. Study design Experimental study design. Methods Ganciclovir solutions (0.5% and 1.0%) prepared by diluting DENOSINE® IV Infusion in saline were stored...
Chapter
Cell based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality for corneal endothelial dysfunction. The proliferative capability of human corneal endothelial cells is severely controlled, thus making the establishment of optimal conditions for th...
Article
Purpose: To develop software to evaluate the fibroblastic morphological changes in cultured human corneal endothelial cells (HCECs) as a quality control measure for use in tissue engineering therapy. Methods: Software was designed to recognize cell borders, to approximate cell shape as an ellipse, and to calculate the aspect ratio of the ellipse...
Article
Full-text available
Purpose: We have performed clinical research on cell-based therapy for corneal endothelial decompensation since 2013. The purpose of this study was to investigate the usefulness of a p38 MAPK inhibitor for promoting proliferation of human corneal endothelial cells (HCECs). Methods: HCECs were cultured in media supplemented with various low-molec...
Article
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 therapeut...
Article
Purpose: The aim of this study was to investigate the existence of presumed immune cells observed by contact specular microscopy in patients who underwent penetrating keratoplasty (PK) and Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: This cross-sectional study was conducted on consecutive patients who underwent follow-...
Article
Purpose: To assess corneal endothelial cell loss after penetrating keratoplasty (PK) treatment for laser iridotomy (LI)-induced bullous keratopathy (BK). Methods: A retrospective study conducted on consecutive patients who underwent PK between March 2000 and December 2011. Patients who had undergone more than 24 months of follow-up were included...
Article
Purpose: To evaluate the effect of corneal vesicles in patients with posterior corneal vesicles (PCV) on corneal endothelial cell (CEC) density and the acquisition of amblyopia. Methods: In this retrospective study of patients with PCV (18 eyes of 14 patients), CEC density was examined by noncontact specular microscopy during each follow-up exam...
Article
Full-text available
Purpose: This study investigates the possible role of the filtration bleb in the continuous decrease in corneal endothelial cell (CEC) density observed following trabeculectomy. Methods: This study involved 51 eyes of 37 glaucoma patients who underwent trabeculectomy. The CEC density was determined by contact specular microscopy in three areas:...
Article
Full-text available
Purpose: The cell-cell adhesion molecules, cadherins and nectins, are involved in the formation of adherens junctions. However, involvement of nectins in the corneal endothelium has not yet been established. This study investigated the involvement of nectins in adherens junctions of the corneal endothelium. Methods: Nectin and cadherin expressio...
Article
Full-text available
Corneal transparency is maintained by the corneal endothelium through its pump and barrier function. Severe corneal endothelial damage results in dysregulation of water flow and eventually causes corneal haziness and deterioration of visual function. In 2013, we initiated clinical research of cell-based therapy for treating corneal decompensation....
Data
Data set of Fig 5B–5E. (XLSX)
Article
Full-text available
Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive bilateral disease of corneal endothelium in which accumulation of extracellular matrix (ECM) and loss of corneal endothelial cells (CECs) are phenotypic features. The corneal endothelium maintains corneal transparency by regulating water hydration; consequently, corneal endothelial...
Article
Full-text available
Aim To investigate the viability of donor corneal endothelial cells (CECs) preserved in storage media by histological examination. Methods Twenty-eight donor corneas were obtained from SightLife Eye Bank (Seattle, Washington), and redundant peripheral portions of those corneas were used for histological examination after removal of the centre corn...
Article
Purpose: To develop analysis software for cultured human corneal endothelial cells (HCECs). Methods: Software was designed to recognize cell borders and to provide parameters such as cell density, coefficient of variation, and polygonality of cultured HCECs based on phase contrast images. Cultured HCECs with high or low cell density were incubat...
Article
Full-text available
Purpose The purpose of this study was to investigate the feasibility of poly lactic/glycolic acid (PLGA) as a drug delivery carrier of Rho kinase (ROCK) inhibitor for the treatment of corneal endothelial disease. Method ROCK inhibitor Y-27632 and PLGA were dissolved in water with or without gelatin (W1), and a double emulsion [(W1/O)/W2] was forme...
Article
Full-text available
Purpose: The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. Methods: Descemet's membranes with corn...
Article
Full-text available
Optimization of culture conditions for human limbal epithelial stem/progenitor cells (LEPC) that incorporate the in vivo cell-matrix interactions are essential to enhance LEPC ex vivo-expansion and transplantation efficiency. Here, we investigate the efficacy of laminin (LN) isoforms preferentially expressed in the limbal niche as culture matrices...
Article
Full-text available
Purpose: We have begun a clinical trial of a cell-based therapy for corneal endothelial dysfunction in Japan. The purpose of this study was to investigate the usefulness of a p38 MAPK inhibitor for prevention cellular senescence in cultivated human corneal endothelial cells (HCECs). Methods: HCECs of 10 donor corneas were divided and cultured wi...
Article
Full-text available
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 subs...
Article
Purpose: The aim of this study was to evaluate which amino acid(s) among the 20 standard protein amino acids is indispensable for the survival of cultured human corneal endothelial cells (HCECs). Methods: HCECs were cultured in amino acid screening media that were missing 1 specific amino acid, and cell growth was evaluated. After this first sel...
Article
Full-text available
Purpose To examine the effects of transcorneal freezing using a new cryoprobe designed for corneal endothelial surgery. Methods A freezing console employing nitrous oxide as a cryogen was used to cool a series of different cryoprobe tip designs made of silver for high thermal conductivity. In vitro studies were conducted on 426 porcine corneas, fo...
Article
Full-text available
Purpose: Corneal endothelial cell density undergoes a progressive decrease for many years after transplantation, eventually threatening patients with late endothelial failure. The purpose of this study was to investigate the possibility of an immunologic response in successfully grafted corneal endothelium. Methods: The corneal endothelium of pa...
Data
SUPPLEMENTAL TABLE 1. Grading system for corneal opacification and conjunctival hyperemia modified from Sotozono et al. [17].
Article
Full-text available
Purpose: Rho kinase (ROCK) pathways control fundamental cell functions, making ROCK an important therapeutic target in several pathophysiologic conditions. The purpose of this study was to investigate whether inhibition of ROCK can suppress apoptosis of the corneal endothelium and to determine the role of ROCK signaling in regulating apoptosis. M...
Article
Background: The cornea is transparent tissue that serves as the window of the eye, allowing light to enter from the outer environment. The corneal endothelium maintains corneal transparency; thus, its dysfunction results in corneal haziness and causes severe vision loss. The only available therapeutic choice for treating corneal endothelial dysfun...
Article
Purpose: The aim of this study was to evaluate the effect of trabeculotomy (TLO) on glaucoma and endothelial cell loss after penetrating keratoplasty (PK). Methods: A retrospective study was conducted on consecutive patients who underwent PK and in whom more than 24 months of follow-up was available. Patients were categorized into the PK+TLO gro...
Article
Purpose To observe the most peripheral region of the corneal endothelial cell (CEC) layer as long as optically recordable by use of a prototype slit-scanning wide-field contact specular microscope and produce a panoramic image to evaluate the variation of CEC density with ageing. Design Observational case series study. Methods This study involved...
Article
Full-text available
The corneal endothelium maintains corneal transparency by its pump and barrier functions; consequently, its decompensation due to any pathological reason causes severe vision loss due to corneal haziness. Corneal transplantation is the only therapeutic choice for treating corneal endothelial dysfunction, but associated problems, such as a shortages...
Data
Composition table of cell therapy vehicle (CTV). This supporting table provides composition of CTV. (PDF)
Data
Participant-level data. This supporting information file provides participant-level data. (XLSX)
Article
Full-text available
The corneal endothelium maintains corneal transparency; consequently, its dysfunction causes severe vision loss. Tissue engineering-based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality. We conducted a preclinical study for cell-based therapy...
Article
Full-text available
Purpose: Ripasudil (Glanatec), a selective rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved as a glaucoma and ocular hypertension treatment in Japan in 2014. The purpose of this study was to investigate the feasibility of using ripasudil eye drops to treat corneal endothelial injuries. Methods: Cultured human c...
Article
Full-text available
Purpose: Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known...
Article
Full-text available
The corneal endothelium is essential for maintaining corneal transparency; therefore, corneal endothelial dysfunction causes serious vision loss. Tissue engineering-based therapy is potentially a less invasive and more effective therapeutic modality. We recently started a first-in-man clinical trial of cell-based therapy for treating corneal endoth...
Article
Full-text available
Purpose: The purpose of this study was to investigate the feasibility of using Rho-associated kinase (ROCK) inhibitor eye drops for treating severe corneal endothelial damage due to surgical invasion. Methods: A rabbit corneal endothelial damage model was created by mechanically scraping half the area of the corneal endothelium of eighteen eyes...
Article
Full-text available
Purpose: To investigate the effect and safety of a selective Rho kinase inhibitor, ripasudil 0.4% eye drops, on corneal endothelial cells of healthy subjects. Design: Prospective, interventional case series. Methods: In this study, 6 healthy subjects were administered ripasudil 0.4% in the right eye twice daily for 1 week. Morphological change...
Article
Full-text available
Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is a major cause of corneal transplantation. It is characterized by abnormal deposition of extracellular matrix (ECM), such as corneal guttae, accompanied by a loss of endothelial cells. Although recent studies have revealed several genomic factors, the molecula...