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Wen Y, Chen Z, McAlinden C, Zhou X, Huang J. Recent advances in corneal neovascularization imaging. Exp Eye Res 2024; 244:109930. [PMID: 38750782 DOI: 10.1016/j.exer.2024.109930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/25/2024] [Accepted: 05/12/2024] [Indexed: 05/19/2024]
Abstract
Corneal neovascularization (CoNV) is a vision-threatening ocular disease commonly secondary to infectious, inflammatory, and traumatic etiologies. Slit lamp photography, in vivo confocal microscopy, angiography, and optical coherence tomography angiography (OCTA) are the primary diagnostic tools utilized in clinical practice to evaluate the vasculature of the ocular surface. However, there is currently a dearth of comprehensive literature that reviews the advancements in imaging technology for CoNV administration. Initially designed for retinal vascular imaging, OCTA has now been expanded to the anterior segment and has shown promising potential for imaging the conjunctiva, cornea, and iris. This expansion allows for the quantitative monitoring of the structural and functional changes associated with CoNV. In this review, we emphasize the impact of algorithm optimization in anterior segment-optical coherence tomography angiography (AS-OCTA) on the diagnostic efficacy of CoNV. Through the analysis of existing literature, animal model assessments are further reported to investigate its pathological mechanism and exhibit remarkable therapeutic interventions. In conclusion, AS-OCTA holds broad prospects and extensive potential for clinical diagnostics and research applications in CoNV.
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Affiliation(s)
- Yinuo Wen
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; Key laboratory of Myopia and Related Eye Diseases, NHC; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Zhongxing Chen
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; Key laboratory of Myopia and Related Eye Diseases, NHC; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Colm McAlinden
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; Key laboratory of Myopia and Related Eye Diseases, NHC; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China; Corneo Plastic Unit & Eye Bank, Queen Victoria Hospital, East Grinstead, UK
| | - Xingtao Zhou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; Key laboratory of Myopia and Related Eye Diseases, NHC; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
| | - Jinhai Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; Key laboratory of Myopia and Related Eye Diseases, NHC; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China.
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2
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Wu D, Chan KE, Lim BXH, Lim DKA, Wong WM, Chai C, Manotosh R, Lim CHL. Management of corneal neovascularization: Current and emerging therapeutic approaches. Indian J Ophthalmol 2024; 72:S354-S371. [PMID: 38648452 PMCID: PMC467007 DOI: 10.4103/ijo.ijo_3043_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/16/2023] [Accepted: 12/25/2023] [Indexed: 04/25/2024] Open
Abstract
Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV.
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Affiliation(s)
- Duoduo Wu
- Department of Ophthalmology, National University Hospital, Singapore
| | - Kai En Chan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Blanche Xiao Hong Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Dawn Ka-Ann Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wendy Meihua Wong
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Charmaine Chai
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ray Manotosh
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chris Hong Long Lim
- Department of Ophthalmology, National University Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
- Singapore Eye Research Institute, Singapore
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3
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Kumar R, Sinha NR, Mohan RR. Corneal gene therapy: Structural and mechanistic understanding. Ocul Surf 2023; 29:279-297. [PMID: 37244594 PMCID: PMC11926995 DOI: 10.1016/j.jtos.2023.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 05/29/2023]
Abstract
Cornea, a dome-shaped and transparent front part of the eye, affords 2/3rd refraction and barrier functions. Globally, corneal diseases are the leading cause of vision impairment. Loss of corneal function including opacification involve the complex crosstalk and perturbation between a variety of cytokines, chemokines and growth factors generated by corneal keratocytes, epithelial cells, lacrimal tissues, nerves, and immune cells. Conventional small-molecule drugs can treat mild-to-moderate traumatic corneal pathology but requires frequent application and often fails to treat severe pathologies. The corneal transplant surgery is a standard of care to restore vision in patients. However, declining availability and rising demand of donor corneas are major concerns to maintain ophthalmic care. Thus, the development of efficient and safe nonsurgical methods to cure corneal disorders and restore vision in vivo is highly desired. Gene-based therapy has huge potential to cure corneal blindness. To achieve a nonimmunogenic, safe and sustained therapeutic response, the selection of a relevant genes, gene editing methods and suitable delivery vectors are vital. This article describes corneal structural and functional features, mechanistic understanding of gene therapy vectors, gene editing methods, gene delivery tools, and status of gene therapy for treating corneal disorders, diseases, and genetic dystrophies.
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Affiliation(s)
- Rajnish Kumar
- Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, 65201, USA; One-health One-medicine Vision Research Program, Departments of Veterinary Medicine and Surgery & Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA; Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow campus, UP, 226028, India
| | - Nishant R Sinha
- Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, 65201, USA; One-health One-medicine Vision Research Program, Departments of Veterinary Medicine and Surgery & Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Rajiv R Mohan
- Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, 65201, USA; One-health One-medicine Vision Research Program, Departments of Veterinary Medicine and Surgery & Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA; Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO, 65212, USA.
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4
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Posarelli M, Romano D, Tucci D, Giannaccare G, Scorcia V, Taloni A, Pagano L, Borgia A. Ocular-Surface Regeneration Therapies for Eye Disorders: The State of the Art. BIOTECH 2023; 12:48. [PMID: 37366796 DOI: 10.3390/biotech12020048] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/28/2023] Open
Abstract
The ocular surface is a complex structure that includes cornea, conjunctiva, limbus, and tear film, and is critical for maintaining visual function. When the ocular-surface integrity is altered by a disease, conventional therapies usually rely on topical drops or tissue replacement with more invasive procedures, such as corneal transplants. However, in the last years, regeneration therapies have emerged as a promising approach to repair the damaged ocular surface by stimulating cell proliferation and restoring the eye homeostasis and function. This article reviews the different strategies employed in ocular-surface regeneration, including cell-based therapies, growth-factor-based therapies, and tissue-engineering approaches. Dry eye and neurotrophic keratopathy diseases can be treated with nerve-growth factors to stimulate the limbal stem-cell proliferation and the corneal nerve regeneration, whereas conjunctival autograft or amniotic membrane are used in subjects with corneal limbus dysfunction, such as limbal stem-cell deficiency or pterygium. Further, new therapies are available for patients with corneal endothelium diseases to promote the expansion and migration of cells without the need of corneal keratoplasty. Finally, gene therapy is a promising new frontier of regeneration medicine that can modify the gene expression and, potentially, restore the corneal transparency by reducing fibrosis and neovascularization, as well as by stimulating stem-cell proliferation and tissue regeneration.
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Affiliation(s)
- Matteo Posarelli
- St. Paul's Eye Unit, Department of Corneal Diseases, Royal Liverpool University Hospital, Liverpool L7 8YE, UK
- Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy
| | - Davide Romano
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, 25123 Brescia, Italy
- Eye Unit, University Hospitals of Leicester, NHS Trust, Leicester LE1 5WW, UK
| | - Davide Tucci
- Department of Biomedical and Surgical Sciences, Section of Ophthalmology, S. Maria Della Misericordia Hospital, University of Perugia, 06123 Perugia, Italy
| | - Giuseppe Giannaccare
- Department of Ophthalmology, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Scorcia
- Department of Ophthalmology, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Andrea Taloni
- Department of Ophthalmology, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Luca Pagano
- St. Paul's Eye Unit, Department of Corneal Diseases, Royal Liverpool University Hospital, Liverpool L7 8YE, UK
| | - Alfredo Borgia
- St. Paul's Eye Unit, Department of Corneal Diseases, Royal Liverpool University Hospital, Liverpool L7 8YE, UK
- Eye Unit, Humanitas-Gradenigo Hospital, 10153 Turin, Italy
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5
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RNA-targeting strategies as a platform for ocular gene therapy. Prog Retin Eye Res 2023; 92:101110. [PMID: 35840489 DOI: 10.1016/j.preteyeres.2022.101110] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/28/2022] [Accepted: 07/06/2022] [Indexed: 02/01/2023]
Abstract
Genetic medicine is offering hope as new therapies are emerging for many previously untreatable diseases. The eye is at the forefront of these advances, as exemplified by the approval of Luxturna® by the United States Food and Drug Administration (US FDA) in 2017 for the treatment of one form of Leber Congenital Amaurosis (LCA), an inherited blindness. Luxturna® was also the first in vivo human gene therapy to gain US FDA approval. Numerous gene therapy clinical trials are ongoing for other eye diseases, and novel delivery systems, discovery of new drug targets and emerging technologies are currently driving the field forward. Targeting RNA, in particular, is an attractive therapeutic strategy for genetic disease that may have safety advantages over alternative approaches by avoiding permanent changes in the genome. In this regard, antisense oligonucleotides (ASO) and RNA interference (RNAi) are the currently popular strategies for developing RNA-targeted therapeutics. Enthusiasm has been further fuelled by the emergence of clustered regularly interspersed short palindromic repeats (CRISPR)-CRISPR associated (Cas) systems that allow targeted manipulation of nucleic acids. RNA-targeting CRISPR-Cas systems now provide a novel way to develop RNA-targeted therapeutics and may provide superior efficiency and specificity to existing technologies. In addition, RNA base editing technologies using CRISPR-Cas and other modalities also enable precise alteration of single nucleotides. In this review, we showcase advances made by RNA-targeting systems for ocular disease, discuss applications of ASO and RNAi technologies, highlight emerging CRISPR-Cas systems and consider the implications of RNA-targeting therapeutics in the development of future drugs to treat eye disease.
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Cui Y, Huo Y, Li Z, Qiu Y, Yang Q, Chen Z, Fan S, Huang X, Hao J, Kang L, Liang G. VEGF-targeted scFv inhibits corneal neovascularization via STAT3 pathway in alkali burn model. Colloids Surf A Physicochem Eng Asp 2022. [DOI: 10.1016/j.colsurfa.2022.130764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Yuan X, Wu H, Li X, Chen L, Xiao Y, Chen Z, Liu G, Lu P. SDF‑1α/CXCR4 signaling promotes capillary tube formation of human retinal vascular endothelial cells by activating ERK1/2 and PI3K pathways in vitro. Mol Med Rep 2022; 26:305. [PMID: 35946444 PMCID: PMC9435019 DOI: 10.3892/mmr.2022.12821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 06/09/2022] [Indexed: 11/06/2022] Open
Abstract
The purpose of this study is to address the effect and mechanism of stromal cell‑derived factor‑1 (SDF‑1)α/chemokine (C‑X‑C motif) receptor 4 (CXCR4) signaling on capillary tube formation of human retinal vascular endothelial cells (HRECs). The expression of CXCR4 in HRECs was quantified by reverse transcription (RT‑PCR) and western blotting. The effects of SDF‑1α/CXCR4 signaling in capillary tube formation and migration of HRECs was examined using three‑dimensional Matrigel assay and wound scratching assay respectively in vitro. Cell proliferation of HRECs was examined using cell counting kit (CCK)‑8 assay in the presence of different concentrations of SDF‑1α protein. The effect of SDF‑1α/CXCR4 signaling in HREC expression of VEGF, basic fibroblast growth factor (bFGF), IL‑8 and intercellular cell adhesion molecule (ICAM)‑1 was examined using RT‑PCR and western blotting. RT‑PCR and western blot analysis revealed CXCR4 was expressed in HRECs. The number of intact capillary tubes formed by HRECs in the presence of SDF‑1α was markedly more compared with a PBS treated control group. However, it was reduced with treatment with an CXCR4 antagonist. Wound scratching assay showed a significant increase in the number of migrated HRECs under SDF‑1α stimulation and the number was reduced with treatment with an CXCR4 antagonist. RT‑PCR and western blotting showed that SDF‑1α significantly promoted VEGF, bFGF, IL‑8 and ICAM‑1 expression in HRECs. The proliferation of HRECs in the presence of SDF‑1α was promoted in a dosage‑dependent manner. SDF‑1α/CXCR4 signaling can increase HREC capillary tube formation through promoting HREC migration, proliferation and expression of VEGF, bFGF, IL‑8 and ICAM‑1.
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Affiliation(s)
- Xianbin Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Hongya Wu
- Jiangsu Key Laboratory of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xin Li
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Lei Chen
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yanhui Xiao
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhigang Chen
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Gaoqin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Peirong Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Nozari N, Biazar E, Kamalvand M, Keshel SH, Shirinbakhsh S. Photo Cross-linkable Biopolymers for Cornea Tissue Healing. Curr Stem Cell Res Ther 2021; 17:58-70. [PMID: 34269669 DOI: 10.2174/1574888x16666210715112738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/11/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Light can act as an effective and strong agent for the cross-linking of biomaterials and tissues and is recognized as a safe substitute for chemical cross-linkers to modify mechanical and physical properties and promote biocompatibility. This review focuses on the research about cross-linked biomaterials with different radiation sources such as Laser or Ultraviolet (UV) that can be applied as scaffolds, controlled release systems, and tissue adhesives for cornea healing and tissue regeneration.
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Affiliation(s)
- Negar Nozari
- Tissue Engineering Group, Department of Biomaterials Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Esmaeil Biazar
- Tissue Engineering Group, Department of Biomaterials Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Mahshad Kamalvand
- Tissue Engineering Group, Department of Biomaterials Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shervin Shirinbakhsh
- Tissue Engineering Group, Department of Biomaterials Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
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Amador C, Shah R, Ghiam S, Kramerov AA, Ljubimov AV. Gene therapy in the anterior eye segment. Curr Gene Ther 2021; 22:104-131. [PMID: 33902406 DOI: 10.2174/1566523221666210423084233] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/14/2021] [Accepted: 04/04/2021] [Indexed: 11/22/2022]
Abstract
This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye including cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We discuss gene delivery systems including viral and non-viral vectors as well as gene editing techniques, mainly CRISPR-Cas9, and epigenetic treatments including antisense and siRNA therapeutics. We also provide a detailed analysis of various anterior segment diseases where gene therapy has been tested with corresponding outcomes. Disease conditions include corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and other ocular surface diseases. Although most of the analyzed results on the use and validity of gene therapy at the ocular surface have been obtained in vitro or using animal models, we also discuss the available human studies. Gene therapy approaches are currently considered very promising as emerging future treatments of various diseases, and this field is rapidly expanding.
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Affiliation(s)
- Cynthia Amador
- Eye Program, Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Ruchi Shah
- Eye Program, Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sean Ghiam
- Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv, Israel
| | - Andrei A Kramerov
- Eye Program, Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Alexander V Ljubimov
- Eye Program, Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Di Iorio E, Barbaro V, Alvisi G, Trevisan M, Ferrari S, Masi G, Nespeca P, Ghassabian H, Ponzin D, Palù G. New Frontiers of Corneal Gene Therapy. Hum Gene Ther 2019; 30:923-945. [PMID: 31020856 DOI: 10.1089/hum.2019.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Corneal diseases are among the most prevalent causes of blindness worldwide. The transparency and clarity of the cornea are guaranteed by a delicate physiological, anatomic, and functional balance. For this reason, all the disorders, including those of genetic origin, that compromise this state of harmony can lead to opacity and eventually vision loss. Many corneal disorders have a genetic etiology, and some are associated with rather rare and complex syndromes. Conventional treatments, such as corneal transplantation, are often ineffective, and to date, many of these disorders are still incurable. Gene therapy carries the promise of being a potential cure for many of these diseases, with solutions and strategies that did not seem possible until a few years ago. With its potential to treat genetic disease by means of deletion, replacement, or editing of a defective gene, the challenge can also be extended to corneal disorders in order to achieve long-term, if not definitive, relief. The aim of this paper is to review the state of the art of the different gene therapy approaches as potential treatments for corneal diseases and the future perspectives for the development of personalized gene-based medicine.
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Affiliation(s)
- Enzo Di Iorio
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Vanessa Barbaro
- 2Fondazione Banca Degli Occhi Del Veneto Onlus, Zelarino, Venezia, Italy
| | - Gualtiero Alvisi
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Marta Trevisan
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Stefano Ferrari
- 2Fondazione Banca Degli Occhi Del Veneto Onlus, Zelarino, Venezia, Italy
| | - Giulia Masi
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Patrizia Nespeca
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Hanieh Ghassabian
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Diego Ponzin
- 2Fondazione Banca Degli Occhi Del Veneto Onlus, Zelarino, Venezia, Italy
| | - Giorgio Palù
- 1Department of Molecular Medicine, University of Padova, Padova, Italy
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Mukwaya A, Jensen L, Peebo B, Lagali N. MicroRNAs in the cornea: Role and implications for treatment of corneal neovascularization. Ocul Surf 2019; 17:400-411. [PMID: 30959113 DOI: 10.1016/j.jtos.2019.04.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/25/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
With no safe and efficient approved therapy available for treating corneal neovascularization, the search for alternative and effective treatments is of great importance. Since the discovery of miRNAs as key regulators of gene expression, knowledge of their function in the eye has expanded continuously, facilitated by high throughput genomic tools such as microarrays and RNA sequencing. Recently, reports have emerged implicating miRNAs in pathological and developmental angiogenesis. This has led to the idea of targeting these regulatory molecules as a therapeutic approach for treating corneal neovascularization. With the growing volume of data generated from high throughput tools applied to study corneal neovascularization, we provide here a focused review of the known miRNAs related to corneal neovascularization, while presenting new experimental data and insights for future research and therapy development.
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Affiliation(s)
- Anthony Mukwaya
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden
| | - Lasse Jensen
- Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Beatrice Peebo
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden
| | - Neil Lagali
- Department of Ophthalmology, Institute for Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden; Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway.
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12
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Liu G, Lu P, Chen L, Zhang W, Wang M, Li D, Zhang X. B-cell leukemia/lymphoma 10 promotes angiogenesis in an experimental corneal neovascularization model. Eye (Lond) 2018; 32:1220-1231. [PMID: 29515217 PMCID: PMC6043546 DOI: 10.1038/s41433-018-0039-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 11/25/2017] [Accepted: 01/09/2018] [Indexed: 01/16/2023] Open
Abstract
PURPOSE Corneal neovascularization (CrNV) arises from many causes including corneal inflammatory, infectious, or traumatic insult, and frequently leads to impaired vision. This study seeks to determine the role of B-cell leukemia/lymphoma 10 (BCL-10) in the development of experimental CrNV. METHODS Corneas from BCL-10 knockout (KO) mice and wild-type (WT) mice were burned by sodium hydroxide (NaOH) to create the CrNV model and neovascular formation in the corneas was assessed 2 weeks later. Intracorneal macrophage accumulation and the expression of angiogenic factors were quantified by flow cytometric analysis (FCM) and real-time PCR, respectively. RESULTS The amount of CrNV was determined 2 weeks after alkali burn. Compared to WT mice, the amount of CrNV in BCL-10 KO mice was significantly decreased. FCM revealed that F4/80-positive macrophages were markedly decreased in BCL-10 KO mice compared with WT mice. Reverse transcription PCR showed that the mRNA expression levels of intracorneal vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (bFGF) and monocyte chemotactic protein 1 were reduced in BCL-10 KO mice compared with WT mice. CONCLUSION BCL-10 KO mice exhibited reduced alkali-induced CrNV by suppressing intracorneal macrophage infiltration, which subsequently led to decreased VEGF-A and bFGF expression, suggesting that BCL-10 may become a potential clinical intervening target of CrNV.
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Affiliation(s)
- Gaoqin Liu
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Peirong Lu
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China.
- Jiangsu Key Laboratory of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Lei Chen
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenpeng Zhang
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Mengjiao Wang
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dan Li
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Key Laboratory of Clinical Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, the First Affiliated Hospital of Soochow University, Suzhou, China
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Liu S, Romano V, Steger B, Kaye SB, Hamill KJ, Willoughby CE. Gene-based antiangiogenic applications for corneal neovascularization. Surv Ophthalmol 2018; 63:193-213. [DOI: 10.1016/j.survophthal.2017.10.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 10/09/2017] [Accepted: 10/12/2017] [Indexed: 12/22/2022]
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14
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Park H, Kim BS. Effect of Fucoidan on Angiogenesis and Gene Expression in Human Umbilical Vein Endothelial Cells. KOREAN JOURNAL OF CLINICAL LABORATORY SCIENCE 2017. [DOI: 10.15324/kjcls.2017.49.4.323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Ho Park
- Department of Clinical Laboratory Science, Wonkwang Health Science University, Iksan, Korea
| | - Beom-Su Kim
- Carbon Nano Convergence Technology Center for Next Generation Engineers, Chonbuk National University, Jeonju, Korea
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Liu G, Wu H, Chen L, Xu J, Wang M, Li D, Lu P. Effects of interleukin-17 on human retinal vascular endothelial cell capillary tube formation in vitro. Mol Med Rep 2017; 16:865-872. [PMID: 28560397 DOI: 10.3892/mmr.2017.6623] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 03/10/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effect of and mechanism underlying interleukin (IL)‑17 on human retinal vascular endothelial cell (HREC) capillary tube formation in vitro. The expression of IL‑17 receptor (IL‑17R) in human HRECs was quantified using reverse transcriptase‑polymerase chain reaction (RT‑PCR) and western blot analyses. The roles of IL‑17 in HREC migration and capillary tube formation were detected using a wound scratching assay and three‑dimensional Matrigel assay, respectively, in vitro. HREC proliferation was examined using a cell counting kit‑8 assay with administration of serial doses of IL‑17. The effects of IL‑17 on the expression of vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule (ICAM)‑1, IL‑6 and IL‑8 in HRECs were evaluated using RT‑PCR and western blot analyses. The results revealed that the HRECs expressed IL‑17R, and the number of intact capillary tubes formed by HRECs in the presence of IL‑17 was markedly higher, compared with that in the blank control group. The wound scratching assay showed that the numbers of migrated HRECs stimulated with IL‑17 at concentrations of 100 or 500 ng/ml were significantly higher, compared with the number in the control group. The RT‑PCR and western blot analyses showed that IL‑17 significantly promoted the expression of VEGF, ICAM‑1, IL‑6 and IL‑8 by the HRECs. The proliferation of HRECs in the presence of IL‑17 was also significantly increased. Therefore, IL‑17 increased HREC capillary tube formation through promoting HREC migration, proliferation, and expression levels of VEGF, ICAM‑1, IL‑6 and IL-8.
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Affiliation(s)
- Gaoqin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Hongya Wu
- Jiangsu Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Lei Chen
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jing Xu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Mengjiao Wang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Dan Li
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Peirong Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Liu G, Wu H, Lu P, Zhang X. Interleukin (IL)-17A Promotes Angiogenesis in an Experimental Corneal Neovascularization Model. Curr Eye Res 2016; 42:368-379. [PMID: 27419340 DOI: 10.1080/02713683.2016.1196705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Gaoqin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- Jiangsu Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Hongya Wu
- Jiangsu Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Peirong Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- Jiangsu Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Xueguang Zhang
- Jiangsu Clinical Immunology Institute, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
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Chen SJ, Lee CJ, Lin TB, Liu HJ, Huang SY, Chen JZ, Tseng KW. Inhibition of Ultraviolet B-Induced Expression of the Proinflammatory Cytokines TNF-α and VEGF in the Cornea by Fucoxanthin Treatment in a Rat Model. Mar Drugs 2016; 14:13. [PMID: 26751458 PMCID: PMC4728510 DOI: 10.3390/md14010013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 12/21/2015] [Accepted: 12/31/2015] [Indexed: 11/16/2022] Open
Abstract
Ultraviolet B (UVB) irradiation is the most common cause of radiation damage to the eyeball and is a risk factor for human corneal damage. We determined the protective effect of fucoxanthin, which is a carotenoid found in common edible seaweed, on ocular tissues against oxidative UVB-induced corneal injury. The experimental rats were intravenously injected with fucoxanthin at doses of 0.5, 5 mg/kg body weight/day or with a vehicle before UVB irradiation. Lissamine green for corneal surface staining showed that UVB irradiation caused serious damage on the corneal surface, including severe epithelial exfoliation and deteriorated epithelial smoothness. Histopathological lesion examination revealed that levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF), significantly increased. However, pretreatment with fucoxanthin inhibited UVB radiation-induced corneal disorders including evident preservation of corneal surface smoothness, downregulation of proinflammatory cytokine expression, and decrease of infiltrated polymorphonuclear leukocytes from UVB-induced damage. Moreover, significant preservation of the epithelial integrity and inhibition of stromal swelling were also observed after UVB irradiation in fucoxanthin-treated groups. Pretreatment with fucoxanthin may protect against UVB radiation-induced corneal disorders by inhibiting expression of proinflammatory factors, TNF-α, and VEGF and by blocking polymorphonuclear leukocyte infiltration.
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Affiliation(s)
- Shiu-Jau Chen
- Department of Neurosurgery, Mackay Memorial Hospital, Taipei 10449, Taiwan.
| | - Ching-Ju Lee
- Internal Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei 24213, Taiwan.
| | - Tzer-Bin Lin
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11049, Taiwan.
| | - Hsiang-Jui Liu
- Department of Optometry, Mackay Junior College of Medicine, Nursing, and Management, New Taipei 11260, Taiwan.
| | - Shuan-Yu Huang
- School of Optometry, College of Medical Sciences and Technology, Chung Shan Medical University, Taichung 40201, Taiwan.
| | - Jia-Zeng Chen
- School of Optometry, College of Medical Sciences and Technology, Chung Shan Medical University, Taichung 40201, Taiwan.
| | - Kuang-Wen Tseng
- Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan.
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Abdelfattah NS, Amgad M, Zayed AA, Salem H, Elkhanany AE, Hussein H, Abd El-Baky N. Clinical correlates of common corneal neovascular diseases: a literature review. Int J Ophthalmol 2015; 8:182-93. [PMID: 25709930 DOI: 10.3980/j.issn.2222-3959.2015.01.32] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 11/19/2014] [Indexed: 12/14/2022] Open
Abstract
A large subset of corneal pathologies involves the formation of new blood and lymph vessels (neovascularization), leading to compromised visual acuity. This article aims to review the clinical causes and presentations of corneal neovascularization (CNV) by examining the mechanisms behind common CNV-related corneal pathologies, with a particular focus on herpes simplex stromal keratitis, contact lenses-induced keratitis and CNV secondary to keratoplasty. Moreover, we reviewed CNV in the context of different types of corneal transplantation and keratoprosthesis, and summarized the most relevant treatments available so far.
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Affiliation(s)
- Nizar Saleh Abdelfattah
- Doheny Image Reading Center, Doheny Eye Institute, University of California, Los Angeles, 1355 San Pablo Street, Los Angeles, California 90033, USA
| | - Mohamed Amgad
- Faculty of Medicine, Cairo University, Cairo 11956, Egypt
| | - Amira A Zayed
- Department of Surgery, Mayo Clinic, Rochester 55905, MN, USA
| | - Hamdy Salem
- Faculty of Medicine, University of Alexandria, Alexandria 21131, Egypt
| | - Ahmed E Elkhanany
- Department of Medical Oncology, Mayo Clinic, Rochester 55905, MN, USA
| | - Heba Hussein
- Faculty of Oral and Dental Medicine, Cairo University, Cairo 11956, Egypt
| | - Nawal Abd El-Baky
- Antibody Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, Alexandria 21934, Egypt
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Liu G, Zhang W, Xiao Y, Lu P. Critical Role of IP-10 on Reducing Experimental Corneal Neovascularization. Curr Eye Res 2014; 40:891-901. [PMID: 25309995 DOI: 10.3109/02713683.2014.968934] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM AND SCOPE To address the role of interferon-induced protein of 10 kDa (IP-10) in the course of corneal neovascularization (CrNV) in a mouse model of experimental corneal neovascularization. MATERIAL AND METHOD BALB/c mice that were 7- to 8-week-old male were included in the study. Corneal injury was induced by NaOH. Mice were randomly divided into 2 groups of IP-10 and vehicle. The alkali-treated eyes received 5 μl of 5 μg/ml IP-10 dissolved in 0.2% sodium hyaluronate for IP-10-treated group, or 5 μl of 0.2% sodium hyaluronate for vehicle-treated group twice a day for 7 days immediately after the alkali injury. 2 weeks after alkali injury, corneas were removed and used for whole mount CD31 staining. The percentages of neovascularization on corneal photographs were examined with digital image analysis. In other experiments, at indicated time intervals, the corneas were removed. Angiogenic factor expression in the early phase after injury was quantified by real-time PCR and western blot. The VEGF expression in macrophages infiltrating into burned corneas was examined by Flow cytometry (FCM) and immunofluorescence. Tube formation and cell proliferation of human retinal endothelial cells (HRECs) were detected after being stimulated with IP-10 in vitro. RESULTS The mRNA and protein expression of IP-10 and C-X-C motif chemokine receptor 3 (CXCR3) was augmented after the alkali injury (p < 0.05). Compared with vehicle-treated mice, IP-10-treated mice exhibited reduced CrNV 2 weeks after injury, as evidenced by diminished CD31-positive areas (p < 0.05). Concomitantly, the intracorneal mRNA and protein expression enhancement of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was lower in IP-10-treated mice than in vehicle-treated mice after injury (p < 0.05). Moreover, IP-10 inhibited HREC tube formation and proliferation in vitro. CONCLUSION IP-10-treated mice exhibited reduced alkali-induced CrNV through decreasing intracorneal VEGF and bFGF expression, and inhibiting endothelial cell proliferation and tube formation.
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Affiliation(s)
- Gaoqin Liu
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University , Suzhou , China and
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20
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Lee CM, Jung WK, Na G, Lee DS, Park SG, Seo SK, Yang JW, Yea SS, Lee YM, Park WS, Choi IW. Inhibitory effects of the platelet-activating factor receptor antagonists, CV-3988 and Ginkgolide B, on alkali burn-induced corneal neovascularization. Cutan Ocul Toxicol 2014; 34:53-60. [PMID: 24754407 DOI: 10.3109/15569527.2014.903573] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE Platelet-activating factor (PAF) has been found in various ocular tissues; the activity of PAF depends on the binding to its specific receptor, PAF-receptor. We investigated the therapeutic effects of PAF-receptor antagonists (CV-3988 and Ginkgolide B) on alkali burn-induced corneal neovascularization (CNV). METHODS CNV was induced by applying a 0.2 N sodium hydroxide (3 µl, NaOH) solution directly on mice corneas. CV-3988 (1 mM/10 µl) and Ginkgolide B (1 mM/10 µl) were administered topically on the corneas three times daily for three consecutive days. CNV was evaluated under a slit-lamp microscope. Corneas were processed for histological, immunohistochemical and reverse transcription polymerase chain reaction analysis. Human umbilical vein endothelial cells were used for the migration and tube formation assay. RESULTS Application of CV-3988 and Ginkgolide B inhibited CNV caused by alkali burn. CV-3988 and Ginkgolide B attenuated the expression of PAF-receptor mRNA. Alkali injury induced a massively increased intraocular mRNA expression of an angiogenic factor in cornea tissues, whereas these increments were attenuated by the application of CV-3988 and Ginkgolide B. CONCLUSIONS CV-3988 and Ginkgolide B reversed opacity and neovascularization in alkali burn-induced corneas. Our findings suggest that CV-3988 and Ginkgolide B may be therapeutically useful in the treatment of CNV and inflammation.
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Affiliation(s)
- Chang-Min Lee
- Department of Internal Medicine, Pulmonary and Critical Care Medicine , New Haven, CT , USA
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Wang Q, Yang J, Tang K, Luo L, Wang L, Tian L, Jiang Y, Feng J, Li Y, Shen B, Lv M, Huang Y. Pharmacological characteristics and efficacy of a novel anti-angiogenic antibody FD006 in corneal neovascularization. BMC Biotechnol 2014; 14:17. [PMID: 24575750 PMCID: PMC3942068 DOI: 10.1186/1472-6750-14-17] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 02/24/2014] [Indexed: 01/19/2023] Open
Abstract
Background Vascular endothelial growth factor (VEGF) is a key angiogenic factors. It plays an important role in both physiologic and pathologic angiogenesis and increases permeability across the vessels. Using antibody phage display technology, we obtained a novel anti-VEGFA IgG, named as FD006. In this study, the pharmacological characteristics and efficacy of FD006 in corneal neovascularization (CoNV) were evaluated. Results FD006 was predicted to have similar binding mode to bevacizumab. Experimental analysis showed that the binding ability of FD006 seemed a little stronger than bevacizumab, for the EC50 of FD006 to bind VEGF analyzed by ELISA was about 0.037 μg/mL while that of bevacizumab was 0.18 μg/mL. Binding kinetics assays showed similar results that FD006 possessed 2-fold higher affinity to bind VEGF than bevacizumab due to slower dissociation rate of FD006; meanwhile, FD006 inhibited the VEGF-induced proliferation of HUVEC with an IC50 value of 0.031 ± 0.0064 μg/ml, which seemed similar or a litter better than bevacizumab (0.047 ± 0.0081 μg/ml). The subconjunctival administration of FD006, bevacizumab or dexamethasone could significantly inhibit the growth of CoNV contrasting to N.S (p < 0.01). At the early stage, FD006 showed better inhibitory effect on the growth of CoNV compared with bevacizumab (p < 0.05). Western blot analysis showed that FD006 could inhibit the expression of VEGF, VEGFR-1, VEGFR-2, MMP-9 and ICAM-1, which could explain its favorable anti-angiogenic activity. Conclusions The pharmacological characteristics of FD006 were similar or even a little better than bevacizumab in inhibiting corneal neovascularization.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Ming Lv
- Department of Ophthalmology, General Hospital of People's Liberation Army, No,28 Fuxing Road, Haidian District, Beijing 100853, China.
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22
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Abstract
Penetrating keratoplasty is the most common type of tissue transplant in humans. Irreversible immune rejection leads to loss of vision and graft failure. This complex immune response further predisposes future corneal transplants to rejection and failure. A diverse armamentarium of surgical and pharmacologic tools is available to improve graft survival. In this review, we will discuss the various gene therapeutic strategies aimed at potentiating the anterior chamber-associated immune deviation to extend graft survival.
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Affiliation(s)
- Pho Nguyen
- The Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Samuel C. Yiu
- The Wilmer Eye Institute, Baltimore, Maryland, USA, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
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Abstract
PURPOSE To review the current literature concerning the use of bevacizumab in treating neovascular disorders affecting the anterior segment ocular structures. METHODS The authors reviewed the literature on anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab for various anterior segment neovascular disorders that was indexed in MEDLINE (up to January 2011). RESULTS Response to bevacizumab anti-VEGF therapy is variable, based on the amount of scarring, the chronicity and extent of corneal neovascularization, the disease process, and the medication formulation and its route of administration. Anti-VEGF agents are especially effective when administered early, before anatomical changes, such as corneal neovascularization and/or angle closure, are established. Neovascularization can recur if the ischemic or inflammatory process is not reversed, so eyes with long-standing diseases, such as autoimmune disorders that involve ongoing inflammation and VEGF production, seem to be less responsive to bevacizumab anti-VEGF therapy. For established neovascularization, combining anti-VEGF agents with the removal of established vessels may be more effective than anti-VEGF therapy alone. Subconjunctival bevacizumab may be more appropriate for focal, deep, and peripheral neovascularization, whereas diffuse superficial neovascularization with central corneal involvement may be best treated via topical application. CONCLUSIONS Besides the widely accepted use of bevacizumab in cancer therapy and chorioretinal neovascularization, the initial, striking, short-term response and patients' high tolerance of local bevacizumab therapy offer encouraging results for the potential role of anti-VEGF agents in treating anterior segment neovascular disorders. Controlled prospective trials are needed to establish the long-term safety, efficacy, and dosing guidelines for the use of anti-VEGF agents in anterior segment neovascularization.
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Abstract
Corneal neovascularization (CNV) may be a physiological response to various stimuli, but a chronic and persistent upregulation of neoangiogenesis can result in pathological CNV. Pathological blood vessels are immature and lack structural integrity, predisposing the cornea to lipid exudation, inflammation, and scarring. CNV can therefore become a potentially blinding condition. In this review, we frame CNV in an epidemiological perspective, consider risk factors for CNV, provide an overview of CNV pathogenesis, and consider the impact of CNV on corneal transplantation. We consider treatments that are of largely historical interest, before reviewing contemporary medical and surgical treatments. Within medical treatments, we report on steroids, nonsteroidal anti-inflammatory agents, antivascular endothelial growth factor agents, and cyclosporine. Within surgical treatments, we report on the use of lasers, photodynamic therapy, superficial keratectomy, and diathermy/cautery-based treatments.
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25
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Zuo L, Fan Y, Wang F, Gu Q, Xu X. A SiRNA Targeting Vascular Endothelial Growth Factor-A Inhibiting Experimental Corneal Neovascularization. Curr Eye Res 2010; 35:375-84. [DOI: 10.3109/02713681003597230] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Hoffart L, Matonti F, Conrath J, Daniel L, Ridings B, Masson GS, Chavane F. Inhibition of corneal neovascularization after alkali burn: comparison of different doses of bevacizumab in monotherapy or associated with dexamethasone. Clin Exp Ophthalmol 2010; 38:346-52. [DOI: 10.1111/j.1442-9071.2010.02252.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model. Gene Ther 2009; 16:973-81. [PMID: 19421232 DOI: 10.1038/gt.2009.50] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Corneal neovascularization can reduce visual acuity. GA-binding protein (GABP) is a transcription factor that regulates the expression of target genes including vascular endothelial growth factor (VEGF) and roundabout4 (Robo4), which participate in pathologic angiogenesis. We assessed whether intraocular injection of the GABP gene affects the growth of new corneal blood vessels in a mouse ocular neovascularization model. Transfection of human GABPalpha and GABPbeta gene (GABPalpha/beta) into human conjunctival epithelial cells resulted in decreased VEGF and Robo4 expression. Three groups of mice underwent chemical and mechanical denudation of the corneal epithelium. Subsequently, two groups were administered subconjunctival injection of lipoplexes carrying plasmid DNA encoding for human GABPalpha/beta or an empty plasmid DNA at 1-week intervals. The third group served as an experimental control. In vivo delivery of human GABPalpha/beta into mouse neovascularized cornea reduced VEGF and Robo4 gene expression. Biomicroscopic examination showed that, at 1 week after one or two injections, GABPalpha/beta-treated eyes had significantly less neovascularized corneal area than did eyes treated with the empty vector. Histologic examination showed significantly less vascularized area and fewer blood vessels in the GABP-treated group at 1 week after injections. However, these angiosuppressive effects were weakened at 2 weeks after injections. Our results indicate that subconjunctival GABP gene delivery delays corneal neovascularization for up to 2 weeks in a mouse model of deliberate corneal injury.
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Inhibition of corneal neovascularization with propolis extract. Arch Med Res 2009; 40:59-61. [PMID: 19064129 DOI: 10.1016/j.arcmed.2008.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2008] [Accepted: 09/22/2008] [Indexed: 01/03/2023]
Abstract
Neovascularization of the normally avascular cornea is seen in many pathological conditions including trauma, corneal transplantation, inflammation and eye diseases. Various growth factors and proteinases are involved in corneal neovascularization. Data supporting a causal role for vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are extensive. Inhibition of angiogenesis is a main strategy for treating corneal neovascularization. Several findings have shown that corneal neovascularization can be reduced by using anti-VEGF and anti-MMPs agents. Efficacy of a propolis extract has been demonstrated for reducing angiogenesis in vitro and in vivo. Propolis extracts containing artepillin C and caffeic acid phenyl ester significantly reduced the number of newly formed vessels and expression of MMPs and VEGF production from various cells. So far, propolis extract is a potential candidate as an anti-angiogenic agent and can inhibit cell proliferation, migration and capillary tube formation. We hypothesize that topical application of propolis is potentially useful for inhibiting corneal neovascularization and restoration of corneal clarity.
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Colella P, Cotugno G, Auricchio A. Ocular gene therapy: current progress and future prospects. Trends Mol Med 2008; 15:23-31. [PMID: 19097940 DOI: 10.1016/j.molmed.2008.11.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 11/04/2008] [Accepted: 11/04/2008] [Indexed: 12/16/2022]
Abstract
As gene therapy begins to produce its first clinical successes, interest in ocular gene transfer has grown owing to the favorable safety and efficacy characteristics of the eye as a target organ for drug delivery. Important advances also include the availability of viral and non-viral vectors that are able to efficiently transduce various ocular cell types, the use of intraocular delivery routes and the development of transcriptional regulatory elements that allow sustained levels of gene transfer in small and large animal models after a single administration. Here, we review recent progress in the field of ocular gene therapy. The first experiments in humans with severe inherited forms of blindness seem to confirm the good safety and efficacy profiles observed in animal models and suggest that gene transfer has the potential to become a valuable therapeutic strategy for otherwise untreatable blinding diseases.
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Affiliation(s)
- Pasqualina Colella
- Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, 80131 Naples, Italy
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30
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Yoeruek E, Ziemssen F, Henke-Fahle S, Tatar O, Tura A, Grisanti S, Bartz-Schmidt KU, Szurman P. Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol 2008; 86:322-8. [PMID: 17995975 DOI: 10.1111/j.1600-0420.2007.01049.x] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
PURPOSE That vascular endothelial growth factor (VEGF) plays a major role in inflammatory angiogenesis has been well established. This pilot study was designed to evaluate experimental treatment with bevacizumab eyedrops in corneal neovascularization induced by alkali burn. The feasibility of topical administration, corneal cell viability and corneal penetration were investigated in an animal model. METHODS Eighteen chinchilla bastard rabbit corneas injured with 1 m NaOH were divided into three groups: untreated, early and late treatment groups. Eyedrops of bevacizumab solution (25 mg/ml) were administered five times daily. Clinical examination under stereoscopic microscope was performed to evaluate corneal opacity, neovascularization, vessel size and oedema. Histopathology was analysed for vessel density and apoptotic reaction. Additionally, intracameral bevacizumab concentration was measured with enzyme-linked immunosorbent assay (ELISA) after repeated topical applications. RESULTS A fast increase in aqueous bevacizumab concentration was achieved when the solution was instilled every minute onto a healthy eye surface. As well as clear anti-angiogenic effects, anti-fibrotic effects were also seen after corneal burn, maintaining corneal transparency. Early treatment of actively growing vessels showed a significantly better outcome, although apoptosis of pre-existing vessels could also be induced by the late treatment. No specific toxicity was seen regarding epithelium, keratocytes or endothelium. CONCLUSIONS The data from this pilot study suggest that bevacizumab eyedrops can sufficiently penetrate the corneal stroma and anterior chamber. When administered soon after alkali burn, bevacizumab seems to significantly reduce corneal damage. Combinations of established treatment regimens with topical bevacizumab might be considered in severe injuries with otherwise devastating prognoses.
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Affiliation(s)
- Efdal Yoeruek
- Department of Ophthalmology, Eberhard-Karls University Tübingen, Germany
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Development of viral vectors with optimal transgene expression for ocular gene therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 613:113-9. [PMID: 18188935 DOI: 10.1007/978-0-387-74904-4_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Striving for ideal viral constructs by modifying its structure, including promoters, would make the viral gene therapy more promising. Further assessment of the promoters and their expression profiles such as those shown in Table 1 and new designs of hybrid promoters may achieve optimal expression features for ocular gene therapies.
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32
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Yu H, Wu J, Li H, Wang Z, Chen X, Tian Y, Yi M, Ji X, Ma J, Huang Q. Inhibition of corneal neovascularization by recombinant adenovirus-mediated sFlk-1 expression. Biochem Biophys Res Commun 2007; 361:946-52. [PMID: 17692288 DOI: 10.1016/j.bbrc.2007.07.114] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 07/18/2007] [Indexed: 11/23/2022]
Abstract
The interaction of vascular endothelial growth factor (VEGF) and its receptors (Flt-1, Flk-1/KDR) is correlated with neovascularization in the eyes. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for inhibiting corneal neovascularization. In this study, we have expressed the cDNA for sFlk-1 under the control of cytomegalovirus immediate-early promoter (CMV) from an E1/partial E3 deleted replication defective recombinant adenovirus, and Ad.sflk-1 expression was determined by Western blotting. We have shown that conditioned media from Ad.sflk-1-infected ARPE-19 cells significantly reduced VEGF-induced human umbilical vein endothelial cells (HUVEC) and murine endothelial cells (SVEC) proliferation in vitro compared with the control vector. In vivo, adenoviral vectors expressing green fluorescent protein alone (Ad.GFP) were utilized to monitor gene transfer to the cornea. Moreover, in the models of corneal neovascularization, the injection of Ad.sflk-1 (10(8)PFU) into the anterior chamber could significantly inhibit angiogenic changes compared with Ad.null-injected and vehicle-injected models. Immunohistochemical analysis showed that corneal endothelial cells and corneal stroma of cauterized rat eyes were efficiently transduced and expressed sFlk-1. These results not only support that adenoviral vectors are capable of high-level transgene expression but also demonstrate that Ad.sflk-1 gene therapy might be a feasible approach for inhibiting the development of corneal neovascularization.
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Affiliation(s)
- Hui Yu
- Central Experimental Laboratory, The First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China
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33
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Klausner EA, Peer D, Chapman RL, Multack RF, Andurkar SV. Corneal gene therapy. J Control Release 2007; 124:107-33. [PMID: 17707107 DOI: 10.1016/j.jconrel.2007.05.041] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2007] [Accepted: 05/15/2007] [Indexed: 12/23/2022]
Abstract
Gene therapy to the cornea can potentially correct inherited and acquired diseases of the cornea. Factors that facilitate corneal gene delivery are the accessibility and transparency of the cornea, its stability ex vivo and the immune privilege of the eye. Initial corneal gene delivery studies characterized the relationship between intraocular modes of administration and location of reporter gene expression. The challenge of achieving effective topical gene transfer, presumably due to tear flow, blinking and low penetration of the vector through epithlelial tight junctions left no alternative but invasive administration to the anterior chamber and corneal stroma. DNA vaccination, RNA interference and gene transfer of cytokines, growth factors and enzymes modulated the corneal microenvironment. Positive results were obtained in preclinical studies for prevention and treatment of corneal graft rejection, neovascularization, haze and herpetic stromal keratitis. These studies, corneal gene delivery systems and modes of administration, and considerations regarding the choice of animal species used are the focus of this review. Opportunities in the field of corneal gene therapy lie in expanding the array of corneal diseases investigated and in the implementation of recent designs of safer vectors with reduced immunogenicity and longer duration of gene expression.
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Affiliation(s)
- Eytan A Klausner
- Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515, United States.
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Shakiba Y, Mostafaie A. Inhibition of corneal neovascularization with a nutrient mixture containing lysine, proline, ascorbic acid, and green tea extract. Arch Med Res 2007; 38:789-91. [PMID: 17845900 DOI: 10.1016/j.arcmed.2007.04.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2007] [Accepted: 04/02/2007] [Indexed: 10/23/2022]
Abstract
Corneal neovascularization is a significant, sight-threatening complication of many ocular surface disorders. Various growth factors and proteinases are involved in corneal neovascularization. The data supporting a causal role for vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are extensive. Inhibition of VEGF and MMPs is a main strategy for treating corneal neovascularization. Several findings have shown that corneal neovascularization can be reduced by using anti-VEGF and anti-MMPs agents. Efficacy of a nutrient mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract has been demonstrated for reducing VEGF and MMPs secretion by various cells. Moreover, NM can inhibit endothelial cell migration and capillary tube formation. We herein note that topical application of NM is potentially useful for inhibiting corneal neovascularization and restoration of corneal clarity. Further investigations in animal models are needed to place NM alongside corneal neovascularization therapeutics.
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Affiliation(s)
- Yadollah Shakiba
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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35
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Dillehay SM. Does the Level of Available Oxygen Impact Comfort in Contact Lens Wear?: A Review of the Literature. Eye Contact Lens 2007; 33:148-55. [PMID: 17502750 DOI: 10.1097/01.icl.0000245572.66698.b1] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Wear of low-Dk/t lenses has long been associated with signs and symptoms indicative of hypoxia and with patient symptoms of dryness and discomfort. Although patient discomfort during soft contact lens wear has been generally attributed to lens dehydration, research studies aimed at verifying that connection have been unsuccessful. With the advent of high-Dk/t silicone hydrogel lenses, not only have improvements in clinical signs of hypoxia been documented, but improvements in patient symptoms of dryness and discomfort also have been documented. This literature review was undertaken to examine historic and current literature to determine whether the level of available oxygen is associated with patient symptoms of dryness and discomfort. METHODS Literature was reviewed related to soft contact lens dehydration, corneal hypoxia, patient symptoms of dryness and discomfort, and current clinical studies of silicone hydrogel lens wear. RESULTS Through the years, the body of knowledge has grown supporting a connection between decreased levels of available oxygen to the cornea caused by low-Dk/t contact lens wear and negative impacts on the signs of corneal health and patient symptoms. CONCLUSIONS Available published literature suggests that many of these changes in patient signs and symptoms seen with low-Dk/t lens wear may be related to an inflammatory response. Clinical studies of high-Dk/t silicone hydrogel lenses further support a significant connection between the level of available oxygen during contact lens wear and improved patient symptoms of comfort, including dryness.
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36
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A potential therapeutic strategy for inhibition of corneal neovascularization with new anti-VEGF agents. Med Hypotheses 2006; 68:799-801. [PMID: 17107753 DOI: 10.1016/j.mehy.2006.06.063] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Accepted: 06/20/2006] [Indexed: 11/20/2022]
Abstract
The factors triggering corneal neovascularization involve various growth factors. The data supporting a causal role for vascular endothelial growth factor (VEGF) in corneal neovascularization are extensive. One possible strategy for treating corneal neovascularization is to inhibit VEGF activity by competitively binding VEGF with a specific neutralizing anti-VEGF antibody. The vireo-retinal service in the recent years enjoyed a high level of success in managing choroidal neovascularization using anti-VEGF strategies. Efficacy and tolerability have been demonstrated for drugs targeting VEGF. We herein hypothesize that topical application of new anti-VEGF agents such as pegaptanib, ranibizumab and bevacizumab are potentially useful for inhibiting corneal neovascularization and restoration of corneal clarity. Further investigations are needed to place these medical treatments alongside corneal neovascularization therapeutics.
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Saika S, Ikeda K, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, Kitano A, Ooshima A, Nakajima Y, Ohnishi Y, Kao WWY. Loss of tumor necrosis factor alpha potentiates transforming growth factor beta-mediated pathogenic tissue response during wound healing. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:1848-60. [PMID: 16723700 PMCID: PMC1606617 DOI: 10.2353/ajpath.2006.050980] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Animal cornea is an avascular transparent tissue that is suitable for research on wound healing-related scarring and neovascularization. Here we show that loss of tumor necrosis factor alpha (TNFalpha) potentiates the undesirable, pathogenic response of wound healing in an alkali-burned cornea in mice. Excessive invasion of macrophages and subsequent formation of a vascularized scar tissue were much more marked in TNFalpha-null knockout (KO) mice than in wild-type mice. Such an unfavorable outcome in KO mice was abolished by Smad7 gene introduction, indicating the involvement of transforming growth factor beta or activin/Smad signaling. Bone marrow transplantation from wild-type mice normalized healing of the KO mice, suggesting the involvement of bone marrow-derived inflammatory cells in this phenomenon. Co-culture experiments showed that loss of TNFalpha in macrophages, but not in fibroblasts, augmented the fibroblast activation as determined by detection of alpha-smooth muscle actin, the hallmark of myofibroblast generation, mRNA expression of collagen Ialpha2 and connective tissue growth factor, and detection of collagen protein. TNFalpha in macrophages may be required to suppress undesirable excessive inflammation and scarring, both of which are promoted by transforming growth factor beta, and for restoration of tissue architecture in a healing alkali-burned cornea in mice.
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Affiliation(s)
- Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan.
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Abstract
Ocular angiogenesis, the formation of new vessels from the existing vascular tree, is a major cause of severe vision loss. It can affect different structures in the eye, including the retina, choroid and cornea. During the last decade our knowledge in the mechanisms underlying ocular angiogenesis has increased dramatically. We have witnessed the identification of key molecules. Many are classified as growth factors due to their biological properties, regulating angiogenesis. This knowledge has propelled the development of a new group of therapeutic tools, the antiangiogenic agents. This review gives an update on the role of growth factors in ocular angiogenesis from both a basic and a clinical perspective.
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Affiliation(s)
- Anders Kvanta
- Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institute, St Erik's Eye Hospital, Stockholm, Sweden.
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Saika S, Ikeda K, Yamanaka O, Miyamoto T, Ohnishi Y, Sato M, Muragaki Y, Ooshima A, Nakajima Y, Kao WWY, Flanders KC, Roberts AB. Expression of Smad7 in mouse eyes accelerates healing of corneal tissue after exposure to alkali. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:1405-18. [PMID: 15855641 PMCID: PMC1606395 DOI: 10.1016/s0002-9440(10)62358-9] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Damage to the cornea from chemical burns is a serious clinical problem that often leads to permanent visual impairment. Because transforming growth factor (TGF)-beta has been implicated in the response to corneal injury, we evaluated the effects of altered TGF-beta signaling in a corneal alkali burn model using mice treated topically with an adenovirus (Ad) expressing inhibitory Smad7 and mice with a targeted deletion of the TGF-beta/activin signaling mediator Smad3. Expression of exogenous Smad7 in burned corneal tissue resulted in reduced activation of Smad signaling and nuclear factor-kappaB signaling via RelA/p65. Resurfacing of the burned cornea by conjunctival epithelium and its differentiation to cornea-like epithelium were both accelerated in Smad7-Ad-treated corneas with suppressed stromal ulceration, opacification, and neovascularization 20 days after injury. Introduction of the Smad7 gene suppressed invasion of monocytes/macrophages and expression of monocyte/macrophage chemotactic protein-1, TGF-beta1, TGF-beta2, vascular endothelial growth factor, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-2 and abolished the generation of myofibroblasts. Although acceleration of healing of the burned cornea was also observed in mice lacking Smad3, the effects on epithelial and stromal healing were less pronounced than those in corneas treated with Smad7. Together these data suggest that overexpression of Smad7 may have effects beyond those of simply blocking Smad3/TGF-beta signaling and may represent an effective new strategy for treatment of ocular burns.
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Affiliation(s)
- Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-0012, Japan.
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Saika S, Ikeda K, Yamanaka O, Flanders KC, Nakajima Y, Miyamoto T, Ohnishi Y, Kao WWY, Muragaki Y, Ooshima A. Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali injury model in mice. J Transl Med 2005; 85:474-86. [PMID: 15696184 DOI: 10.1038/labinvest.3700247] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
An alkali burn in the cornea is a common serious clinical problem often leading to permanent visual impairment. Since transforming growth factor-beta (TGF-beta) is involved in the response to corneal injury, we evaluated the therapeutic effects of adenoviral gene transfer of mouse bone morphogenic protein-7 (BMP-7), which has antagonistic effects on TGF-beta in tissue fibrosis. Burned cornea did not express endogenous BMP-7 mRNA and protein. Resurfacing of the burned cornea by invading conjunctival epithelium was accelerated by adenoviral introduction of BMP-7. Exogenous BMP-7 expression also suppressed myofibroblast generation, appearance of monocytes/macrophages and expression of MCP-1, TGF-betas, and collagen I alpha2 chain in the affected stroma. Ectopic BMP-7 did not suppress stromal neovascularization throughout the interval studied and also did not reduce VEGF mRNA expression at Day 10. Ectopic BMP-7 in burned corneal tissue resulted in activation of Smad1/5/8 signaling and partial suppression of the phospho-Smad2 signal. These data suggest that overexpression of BMP-7 is an effective strategy for treatment of ocular alkali burns.
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Affiliation(s)
- Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University, Kimiidera, Wakayama, Japan.
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Marano RJ, Rakoczy PE. Treatments for choroidal and retinal neovascularization: a focus on oligonucleotide therapy and delivery for the regulation of gene function. Clin Exp Ophthalmol 2005; 33:81-9. [PMID: 15670087 DOI: 10.1111/j.1442-9071.2005.00952.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Blinding eye diseases caused by neovascularization of the retinal tissue are the leading cause of blindness in Western societies. Current treatments, such as laser photocoagulation, are limited in their effectiveness at halting the progression of angiogenesis and are unable to reduce the number of vessels once they have developed. In addition, although complete blindness is often avoided, vision is often permanently impaired by the treatment itself. Several less invasive treatments are being developed and one of these is oligonucleotide gene therapy in which short stretches of nucleotides are being used as inhibitors of key, metabolic processes involved in angiogenesis. Combined with this is the development of new and improved nucleotide chemistries aimed at overcoming many of the problems associated with oligonucleotide gene therapy, such as poor longevity because of endonuclease activity. In addition, advancements in delivery systems have further enhanced the efficacy of oligonucleotide gene therapy by increasing cellular penetration and localizing delivery to specific cell types and organs.
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Affiliation(s)
- Robert J Marano
- Department of Molecular Ophthalmology, Lions Eye Institute, Western Australia, Australia.
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Williams KA, Jessup CF, Coster DJ. Gene therapy approaches to prolonging corneal allograft survival. Expert Opin Biol Ther 2005; 4:1059-71. [PMID: 15268674 DOI: 10.1517/14712598.4.7.1059] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Irreversible immunological rejection is the major cause of human corneal allograft failure and occurs despite the use of topical glucocorticoid immunosuppression. Systemic pharmacological interventions have not found widespread favour in corneal transplantation because of associated morbidities and inadequate demonstration of efficacy. Gene therapy offers tantalising prospects for improving corneal allograft survival, especially in those recipients at high risk of graft rejection. Donor corneas can be gene-modified ex vivo, while in storage prior to implantation, and the relative isolation of the transplanted cornea from the circulation decreases the risk of potential systemic complications. A wide variety of vectors have been found suitable for gene transfer to the cornea. The mechanisms involved in corneal graft rejection have been placed on a relatively secure footing over the past decade and in consequence a number of transgenes with promise for modulating rejection have been identified. However, relatively few studies have thus far demonstrated significant prolongation of corneal allograft survival after gene transfer to the donor cornea. In these instances, the therapeutic protein almost certainly acted at a proximal level in the afferent immune response, within the ocular environs.
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Affiliation(s)
- Keryn A Williams
- Department of Ophthalmology, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, GPO Box 2100, Adelaide SA 5042, Australia.
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Pan X, Wang Y, Zhang M, Pan W, Qi ZT, Cao GW. Effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenoviruses on antiangiogenesis. World J Gastroenterol 2004; 10:1409-14. [PMID: 15133844 PMCID: PMC4656275 DOI: 10.3748/wjg.v10.i10.1409] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the inhibitory effects of endostatin-vascular endothelial growth inhibitor (VEGI151) recombinant adenoviruses on neovascularization.
METHODS: We used recombinant adenoviruses to treat human vascular endothelial cell line ECV304, human hepatocellular carcinoma cell line HepG2, and murine fibroblast cell line L929, in order to study the chimeric gene expression in these cell lines. Chick choriallantic membrane (CAM) model, rabbit inflammatory corneal neovascularization (CNV) model, and liver cancer-bearing nude mice model were employed to investigate the negative biological effect of fusion molecules on neovascularization in vivo.
RESULTS: Western blot showed that the molecular weight of fusion protein was about 41kD after infection of ECV304, HepG2 and L929 cells with supernatant of AdhENDO-VEGI151. The fusion protein showed a specific inhibitory effect on the proliferation of ECV304 cells, but no inhibitory effect on the growth of HepG2 and L929 cells (F = 13112.13, P = 0.0001). In the chick choriallantic membrane (CAM) assay, the expressed fusion protein significantly inhibited neovascularization. Rabbit inflammatory corneal neovasculari-zation (CNV) induced by intrastromal sutures resulted in a uniform neovascular response. In this model, direct subconjunctival injection of AdhENDO-VEGI151 expressed the fusion protein in vivo and suppressed the development of CNV. Topical application of AdhENDO-VEGI151 led to a significant suppression of CNV (F = 1413.11, P = 0.0001), as compared with the control group of AdLacZ. Immunohist-ochemical staining showed the fusion protein dominantly expressed in corneal epithelium. Compared with the control group of AdLacZ (4075.9 ± 1849.9 mm3), the average tumor size of group AdhENDO-VEGI151 reduced in size (487.7 ± 241.2 mm3) (F = 14.80, P = 0.0085), with an inhibition rate of 88.03%. Immunohistochemical staining showed the adenoviruses carried the fusion gene expressed on liver cancer cell membrane. MVD decreased more significantly in treated mice (30.75% ± 3.31%) than in AdLacZ control (50.25% ± 8.65%) (F = 17.72, P = 0.0056) with an inhibition rate of 39%.
CONCLUSION: Fusion protein expressed by recombinant adenoviruses has a significant inhibitory effect on neovasculari-zation.
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Affiliation(s)
- Xin Pan
- Department of Microbiology, Second Military Medical University, Shanghai 200433, China.
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Abstract
Recent advances in the field of ocular gene transfer have led researchers pursuing treatment for age-related macular degeneration and diabetic retinopathy to turn to gene therapy for the answer. Viral vector-mediated delivery of both anti-angiogenic proteins and molecules that inhibit the eye's endogenous pro-angiogenic factors has successfully diminished the pathology of ocular diseases in rodent models. A gene-therapy solution to the debilitating blindness caused by ocular neovascularization may be on the horizon.
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Affiliation(s)
- Samuel J Reich
- FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, The University of Pennsylvania, 310 Stellar Chance Labs, 422 Curie Blvd, Philadelphia, Pennsylvania 19104-6069, USA.
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