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Suleman A, Aluyi-Osa G, Ashipa F, Spadea L, Gagliano C, D’Esposito F, Zeppieri M, Musa M. Autologous blood in the management of ocular surface disorders. World J Exp Med 2024; 14:96412. [PMID: 39713083 PMCID: PMC11551708 DOI: 10.5493/wjem.v14.i4.96412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 10/31/2024] Open
Abstract
Autologous blood therapy has emerged as a promising modality in managing ocular surface disorders. This review provides a comprehensive overview of the current literature regarding the use of autologous blood in ocular surface disorders, encompassing its physiological basis, clinical applications, techniques, challenges, and future perspectives. The ocular surface, comprising the cornea, conjunctiva, and tear film, plays a critical role in maintaining visual function, and its disruption can lead to various pathological conditions. With its rich composition of growth factors, cytokines, and other bioactive molecules, autologous blood offers therapeutic potential in promoting corneal wound healing, reducing inflammation, and improving tear film stability. Clinical studies have demonstrated the efficacy and safety of autologous blood therapy in diverse ocular surface disorders, including persistent epithelial defects, neurotrophic keratopathy, and dry eye disease. However, challenges such as variability in treatment response, adverse effects, and optimal patient selection remain areas of concern. Further research is needed to elucidate the underlying mechanisms of action, refine treatment protocols, and explore synergistic approaches with other therapeutic modalities. Despite these challenges, autologous blood therapy holds promise as a valuable adjunctive treatment option for ocular surface disorders, offering new avenues for improving patient outcomes and quality of life. This review examines the mechanisms underlying ocular surface disorders while discussing existing autologous blood-based therapies for managing these disorders. Current clinical trials are also summarized, and a comparison between autologous blood therapy and conventional eyedrops is attempted. Finally, safe techniques and protocols for autologous blood medicine are elucidated, and adverse effects and future perspectives of this novel therapy are reviewed.
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Affiliation(s)
- Ayuba Suleman
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | - Gladness Aluyi-Osa
- Department of Ophthalmology, Africa Eye Laser Centre, Km 7, Benin 300105, Nigeria
| | | | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, “Sapienza” University of Rome, Rome 00142, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Enna 94100, Italy
- Mediterranean Foundation “G.B. Morgagni”, Catania 95125, Italy
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group Unit, Imperial College, London NW1 5QH, United Kingdom
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Mutali Musa
- Department of Optometry, University of Benin, Benin 3000283, Nigeria
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Bhujel B, Oh SH, Kim CM, Yoon YJ, Chung HS, Ye EA, Lee H, Kim JY. Current Advances in Regenerative Strategies for Dry Eye Diseases: A Comprehensive Review. Bioengineering (Basel) 2023; 11:39. [PMID: 38247916 PMCID: PMC10813666 DOI: 10.3390/bioengineering11010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/17/2023] [Accepted: 12/26/2023] [Indexed: 01/23/2024] Open
Abstract
Dry eye disease (DED) is an emerging health issue affecting millions of individuals annually. Ocular surface disorders, such as DED, are characterized by inflammation triggered by various factors. This condition can lead to tear deficiencies, resulting in the desiccation of the ocular surface, corneal ulceration/perforation, increased susceptibility to infections, and a higher risk of severe visual impairment and blindness. Currently, the clinical management of DED primarily relies on supportive and palliative measures, including the frequent and lifelong use of different lubricating agents. While some advancements like punctal plugs, non-steroidal anti-inflammatory drugs, and salivary gland autografts have been attempted, they have shown limited effectiveness. Recently, there have been promising developments in the treatment of DED, including biomaterials such as nano-systems, hydrogels, and contact lenses for drug delivery, cell-based therapies, biological approaches, and tissue-based regenerative therapy. This article specifically explores the different strategies reported so far for treating DED. The aim is to discuss their potential as long-term cures for DED while also considering the factors that limit their feasibility and effectiveness. These advancements offer hope for more effective and sustainable treatment options in the future.
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Affiliation(s)
| | | | | | | | | | | | | | - Jae-Yong Kim
- Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; (B.B.); (S.-H.O.); (C.-M.K.); (Y.-J.Y.); (H.-S.C.); (E.-A.Y.); (H.L.)
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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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Schulz M, Levy DI, Petropoulos CJ, Bashirians G, Winburn I, Mahn M, Somanathan S, Cheng SH, Byrne BJ. Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy. Mol Ther 2023; 31:616-630. [PMID: 36635967 PMCID: PMC10014285 DOI: 10.1016/j.ymthe.2023.01.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/21/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. Approximately 30%-60% of individuals have pre-existing anti-AAV antibodies. Seroprevalence is impacted by multiple factors, including geography, age, capsid serotype, and assay type. Anti-AAV antibody assays typically measure (1) transduction inhibition by detecting the neutralizing capacity of antibodies and non-antibody neutralizing factors, or (2) total anti-capsid binding antibodies, regardless of neutralizing activity. Presently, there is a paucity of head-to-head data and standardized approaches associating assay results with clinical outcomes. In addition, establishing clinically relevant screening titer cutoffs is complex. Thus, meaningful comparisons across assays are nearly impossible. Although complex, establishing screening assays in routine clinical practice to identify patients with antibody levels that may impact favorable treatment outcomes is achievable for both transduction inhibition and total antibody assays. Formal regulatory approval of such assays as companion diagnostic tests will confirm their suitability for specific recombinant AAV gene therapies. This review covers current approaches to measure anti-AAV antibodies in patient plasma or serum, their potential impact on therapeutic safety and efficacy, and investigative strategies to mitigate the effects of pre-existing anti-AAV antibodies in patients.
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Affiliation(s)
- Martin Schulz
- Pfizer, 235 East 42nd Street, New York, NY 10017, USA
| | - Daniel I Levy
- Pfizer, 235 East 42nd Street, New York, NY 10017, USA
| | | | | | - Ian Winburn
- Pfizer, 235 East 42nd Street, New York, NY 10017, USA
| | - Matthias Mahn
- Pfizer, 235 East 42nd Street, New York, NY 10017, USA
| | | | - Seng H Cheng
- Pfizer, 235 East 42nd Street, New York, NY 10017, USA
| | - Barry J Byrne
- University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
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Gautier B, Meneux L, Feret N, Audrain C, Hudecek L, Kuony A, Bourdon A, Le Guiner C, Blouin V, Delettre C, Michon F. AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification. Mol Ther Methods Clin Dev 2022; 27:1-16. [PMID: 36156877 PMCID: PMC9463184 DOI: 10.1016/j.omtm.2022.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/18/2022] [Indexed: 11/27/2022]
Abstract
Corneal blindness is the fourth leading cause of blindness worldwide. Since corneal epithelium is constantly renewed, non-integrative gene transfer cannot be used to treat corneal diseases. In many of these diseases, the tear film is defective. Tears are a complex biological fluid secreted by the lacrimal apparatus. Their composition is modulated according to the context. After a corneal wound, the lacrimal gland secretes reflex tears, which contain growth factors supporting the wound healing process. In various pathological contexts, the tear composition can support neither corneal homeostasis nor wound healing. Here, we propose to use the lacrimal gland as bioreactor to produce and secrete specific factors supporting corneal physiology. In this study, we use an AAV2/9-mediated gene transfer to supplement the tear film. First, we demonstrate that a single injection of AAV2/9 is sufficient to transduce all epithelial cell types of the lacrimal gland efficiently and widely. Second, we detect no adverse effect after AAV2/9-mediated nerve growth factor expression in the lacrimal gland. Only a transitory increase in tear flow is measured. Remarkably, AAV2/9 induces an important and long-lasting secretion of this growth factor in the tear film. Altogether, our findings provide a new clinically applicable approach to tackle corneal blindness.
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Affiliation(s)
- Benoit Gautier
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
- Corresponding author Benoit Gautier, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France.
| | - Léna Meneux
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Nadège Feret
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Christine Audrain
- TarGeT, Nantes University, INSERM UMR 1089, CHU Nantes, Nantes, France
| | - Laetitia Hudecek
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
- MRI, Biocampus, University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Alison Kuony
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
- Cell Adhesion and Mechanics Lab, Université de Paris, CNRS, Institut Jacques Monod, Paris, France
| | - Audrey Bourdon
- INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France
| | | | - Véronique Blouin
- INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France
| | - Cécile Delettre
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
| | - Frédéric Michon
- Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France
- Corresponding author Frédéric Michon, Institute for Neurosciences of Montpellier, University of Montpellier, INSERM, Montpellier, France.
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Singh VK, Sharma P, Vaksh UKS, Chandra R. Current approaches for the regeneration and reconstruction of ocular surface in dry eye. Front Med (Lausanne) 2022; 9:885780. [PMID: 36213677 PMCID: PMC9544815 DOI: 10.3389/fmed.2022.885780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Significant research revealed the preocular tear film composition and regulations that remain vital for maintaining Ocular surface functional integrity. Inflammation triggered by many factors is the hallmark of Ocular surface disorders or dry eyes syndrome (DES). The tear deficiencies may lead to ocular surface desiccation, corneal ulceration and/or perforation, higher rates of infectious disease, and the risk of severe visual impairment and blindness. Clinical management remains largely supportive, palliative, and frequent, lifelong use of different lubricating agents. However, few advancements such as punctal plugs, non-steroidal anti-inflammatory drugs, and salivary gland autografts are of limited use. Cell-based therapies, tissue engineering, and regenerative medicine, have recently evolved as long-term cures for many diseases, including ophthalmic diseases. The present article focuses on the different regenerative medicine and reconstruction/bioengineered lacrimal gland formation strategies reported so far, along with their limiting factors and feasibility as an effective cure in future.
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Affiliation(s)
- Vimal Kishor Singh
- Department of Biomedical Engineering, Amity School of Engineering and Technology, Amity University, Noida, Uttar Pradesh, India
- *Correspondence: Vimal Kishor Singh ; ;
| | - Pallavi Sharma
- Tissue Engineering and Regenerative Medicine Research Lab, Department of Biomedical Engineering, Amity School of Engineering and Technology, Amity University, Noida, Uttar Pradesh, India
| | - Uttkarsh Kumar Sharma Vaksh
- Tissue Engineering and Regenerative Medicine Research Lab, Department of Biomedical Engineering, Amity School of Engineering and Technology, Amity University, Gurgaon, Haryana, India
| | - Ramesh Chandra
- Institute of Nanomedical Sciences, University of Delhi, Delhi, India
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7
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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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Bastola P, Song L, Gilger BC, Hirsch ML. Adeno-Associated Virus Mediated Gene Therapy for Corneal Diseases. Pharmaceutics 2020; 12:pharmaceutics12080767. [PMID: 32823625 PMCID: PMC7464341 DOI: 10.3390/pharmaceutics12080767] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/14/2022] Open
Abstract
According to the World Health Organization, corneal diseases are the fourth leading cause of blindness worldwide accounting for 5.1% of all ocular deficiencies. Current therapies for corneal diseases, which include eye drops, oral medications, corrective surgeries, and corneal transplantation are largely inadequate, have undesirable side effects including blindness, and can require life-long applications. Adeno-associated virus (AAV) mediated gene therapy is an optimistic strategy that involves the delivery of genetic material to target human diseases through gene augmentation, gene deletion, and/or gene editing. With two therapies already approved by the United States Food and Drug Administration and 200 ongoing clinical trials, recombinant AAV (rAAV) has emerged as the in vivo viral vector-of-choice to deliver genetic material to target human diseases. Likewise, the relative ease of applications through targeted delivery and its compartmental nature makes the cornea an enticing tissue for AAV mediated gene therapy applications. This current review seeks to summarize the development of AAV gene therapy, highlight preclinical efficacy studies, and discuss potential applications and challenges of this technology for targeting corneal diseases.
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Affiliation(s)
- Prabhakar Bastola
- Ophthalmology, University of North Carolina, Chapel Hill, NC 27599, USA; (P.B.); (L.S.); (B.C.G.)
- Gene Therapy Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Liujiang Song
- Ophthalmology, University of North Carolina, Chapel Hill, NC 27599, USA; (P.B.); (L.S.); (B.C.G.)
- Gene Therapy Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Brian C. Gilger
- Ophthalmology, University of North Carolina, Chapel Hill, NC 27599, USA; (P.B.); (L.S.); (B.C.G.)
- Clinical Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Matthew L. Hirsch
- Ophthalmology, University of North Carolina, Chapel Hill, NC 27599, USA; (P.B.); (L.S.); (B.C.G.)
- Gene Therapy Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Correspondence: ; Tel.: +1-919-966-0696
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Song L, Llanga T, Conatser LM, Zaric V, Gilger BC, Hirsch ML. Serotype survey of AAV gene delivery via subconjunctival injection in mice. Gene Ther 2018; 25:402-414. [PMID: 30072815 PMCID: PMC11610513 DOI: 10.1038/s41434-018-0035-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/22/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022]
Abstract
AAV gene therapy approaches in the posterior eye resulted in the first FDA-approved gene therapy-based drug. However, application of AAV vectorology to the anterior eye has yet to enter even a Phase I trial. Furthermore, the simple and safe subconjunctival injection has been relatively unexplored in regard to AAV vector transduction. To determine the utility of this route for the treatment of various ocular disorders, a survey of gene delivery via natural AAV serotypes was performed and correlated to reported cellular attachment factors. AAV serotypes packaged with a self-complementary reporter were administered via subconjunctival injection to WT mice. Subconjunctival injection of AAV vectors was without incidence; however, vector shedding in tears was noted weeks following administration. AAV transduction was serotype dependent in anterior segment tissues including the eye lid, conjunctiva, and cornea, as well as the periocular tissues including muscle. Transgene product in the cornea was highest for AAV6 and AAV8, however, their corneal restriction was remarkably different; AAV6 appeared restricted to the endothelium layer while AAV8 efficiently transduced the stromal layer. Reported AAV cellular receptors were not well correlated to vector transduction; although, in some cases they were conserved among mouse and human ocular tissues. Subconjunctival administration of particular AAV serotypes may be a simple and safe targeted gene delivery route for ocular surface, muscular, corneal, and optic nerve diseases.
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Affiliation(s)
- Liujiang Song
- School of Medicine, Hunan Normal University, Changsha, 422800, Hunan, China
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Ophthalmology, University of North Carolina, Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Telmo Llanga
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Ophthalmology, University of North Carolina, Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Laura M Conatser
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Ophthalmology, University of North Carolina, Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Violeta Zaric
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Brian C Gilger
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC, 27607, USA
| | - Matthew L Hirsch
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Ophthalmology, University of North Carolina, Chapel Hill, Chapel Hill, NC, 27599, USA.
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10
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Gilger BC. Immune Relevant Models for Ocular Inflammatory Diseases. ILAR J 2018; 59:352-362. [DOI: 10.1093/ilar/ily002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 01/18/2018] [Accepted: 01/27/2018] [Indexed: 02/03/2023] Open
Abstract
Abstract
Ocular inflammatory diseases, such as dry eye and uveitis, are common, painful, difficult to treat, and may result in vision loss or blindness. Ocular side effects from the use of antiinflammatory drugs (such as corticosteroids or nonsteroidal antiinflammatories) to treat ocular inflammation have prompted development of more specific and safer medications to treat inflammatory and immune-mediated diseases of the eye. To assess the efficacy and safety of these new therapeutics, appropriate immune-relevant animal models of ocular inflammation are needed. Both induced and naturally-occurring models have been described, but the most valuable for translating treatments to the human eye are the animal models of spontaneous, immunologic ocular disease, such as those with dry eye or uveitis. The purpose of this review is to describe common immune-relevant models of dry eye and uveitis with an overview of the immuno-pathogenesis of each disease and reported evaluation of models from small to large animals. We will also review a selected group of naturally-occurring large animal models, equine uveitis and canine dry eye, that have promise to translate into a better understanding and treatment of clinical immune-relevant ocular disease in man.
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Affiliation(s)
- Brian C Gilger
- Professor of Ophthalmology, Comparative Medicine Institute, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, USA
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11
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Mircheff AK, Wang Y, Schechter JE, Li M, Tong W, Attar M, Chengalvala M, Harmuth J, Prusakiewicz JJ. Multiple Natural and Experimental Inflammatory Rabbit Lacrimal Gland Phenotypes. Ocul Surf 2016; 14:460-483.e3. [PMID: 27423911 PMCID: PMC5065763 DOI: 10.1016/j.jtos.2016.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 06/10/2016] [Accepted: 07/01/2016] [Indexed: 01/25/2023]
Abstract
Purpose To investigate lacrimal gland (LG) immunophysiological and immune-mediated inflammatory process (IMIP) phenotype diversity. Methods Ex vivo matured dendritic cells (mDC) were loaded with acinar cell microparticles (MP). Peripheral blood lymphocytes (PBL) were activated in mixed cell reactions with mDC and injected directly into autologous, unilateral LG (1° ATD-LG) of two rabbit cohorts, one naïve, one immunized with a LG lysate membrane fraction (Pi). Autoimmune IgG titers were assayed by ELISA, MCR PBL stimulation indices (SI) by [3H]-thymidine incorporation. Schirmer tests without and with topical anesthetic (STT-I, STT-IA) and rose Bengal (RB) staining tests were performed. H&E and immunohistochemically stained sections were examined. RNA yields and selected transcript abundances were measured. Immune cell number and transcript abundance data were submitted to Principal Component Analysis (PCA). Results Immunizing Pi dose influenced SI but not IgG titers. STT scores were decreased, and rose Bengal scores increased, by day 118 after immunization. Previous immunization exacerbated scores in 1° ATD-eyes and exacerbated 1° ATD-LG atrophy. IMIP were evident in 2° ATD-LG as well as 1° ATD-LG. PCA described diverse immunophysiological phenotypes in control LG and diverse IMIP phenotypes in ATD-LG. IgG titers and SI pre-adoptive transfer were significantly associated with certain post-adoptive transfer IMIP phenotype features, and certain LG IMIP features were significantly associated with RB and STT IA scores. Conclusions The underlying variability of normal states may contribute to the diversity of experimental IMIP phenotypes. The ability to generate and characterize diverse phenotypes may lead to phenotype-specific diagnostic and therapeutic paradigms.
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Affiliation(s)
- Austin K Mircheff
- Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Yanru Wang
- Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joel E Schechter
- Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Meng Li
- Bioinformatics Service, Norris Medical Library, University of Southern California, Los Angeles, CA, USA
| | - Warren Tong
- Translational Drug Metabolism, Pharmacokinetics and Immunology, Allergan Inc., Irvine, CA, USA
| | - Mayssa Attar
- Translational Drug Metabolism, Pharmacokinetics and Immunology, Allergan Inc., Irvine, CA, USA
| | | | - Joe Harmuth
- Immunology Services, Covance Research Products, Denver, PA, USA
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Farid M, Agrawal A, Fremgen D, Tao J, Chuyi H, Nesburn AB, BenMohamed L. Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease. Ocul Immunol Inflamm 2016; 24:327-47. [PMID: 25535823 PMCID: PMC4478284 DOI: 10.3109/09273948.2014.986581] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Dry eye disease (DED) is a prevalent public health concern that affects up to 30% of adults and is particularly chronic and severe in the elderly. Two interconnected mechanisms cause DED: (1) an age-related dysfunction of lacrimal and meibomian glands, which leads to decreased tear production and/or an increase in tear evaporation; and (2) an age-related uncontrolled inflammation of the surface of the eye triggered by yet-to-be-determined internal immunopathological mechanisms, independent of tear deficiency and evaporation. In this review we summarize current knowledge on animal models that mimic both the severity and chronicity of inflammatory DED and that have been reliably used to provide insights into the immunopathological mechanisms of DED, and we provide an overview of the opportunities and limitations of the rabbit model in investigating the role of both ocular and nasal mucosal immune systems in the immunopathology of inflammatory DED and in testing novel immunotherapies aimed at delaying or reversing the uncontrolled age-related inflammatory DED.
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Affiliation(s)
- Marjan Farid
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
| | - Anshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, USA
| | - Daniel Fremgen
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
| | - Jeremiah Tao
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
| | - He Chuyi
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
| | - Anthony B. Nesburn
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
| | - Lbachir BenMohamed
- Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, USA
- Department of Molecular Biology, University of California Irvine, School of Medicine, Irvine, California, USA
- Biochemistry and Institute for Immunology, University of California Irvine, School of Medicine, Irvine, California, USA
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Dietrich J, Massie I, Roth M, Geerling G, Mertsch S, Schrader S. Development of Causative Treatment Strategies for Lacrimal Gland Insufficiency by Tissue Engineering and Cell Therapy. Part 1: Regeneration of Lacrimal Gland Tissue: Can We Stimulate Lacrimal Gland Renewal In Vivo? Curr Eye Res 2016; 41:1131-42. [DOI: 10.3109/02713683.2016.1148741] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Jana Dietrich
- Labor für Experimentelle Ophthalmologie, University of Düsseldorf, Düsseldorf, Germany
| | - Isobel Massie
- Labor für Experimentelle Ophthalmologie, University of Düsseldorf, Düsseldorf, Germany
| | - Mathias Roth
- Augenklinik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Gerd Geerling
- Augenklinik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Sonja Mertsch
- Labor für Experimentelle Ophthalmologie, University of Düsseldorf, Düsseldorf, Germany
| | - Stefan Schrader
- Labor für Experimentelle Ophthalmologie, University of Düsseldorf, Düsseldorf, Germany
- Augenklinik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
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Mircheff AK, Wang Y, Ding C, Warren DW, Schechter JE. Potentially pathogenic immune cells and networks in apparently healthy lacrimal glands. Ocul Surf 2015; 13:47-81. [PMID: 25557346 DOI: 10.1016/j.jtos.2014.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/05/2014] [Accepted: 06/05/2014] [Indexed: 12/22/2022]
Abstract
Lacrimal glands of people over 40 years old frequently contain lymphocytic infiltrates. Relationships between histopathological presentation and physiological dysfunction are not straightforward. Data from rabbit studies have suggested that at least two immune cell networks form in healthy lacrimal glands, one responding to environmental dryness, the other to high temperatures. New findings indicate that mRNAs for several chemokines and cytokines are expressed primarily in epithelial cells; certain others are expressed in both epithelial cells and immune cells. Transcript abundances vary substantially across glands from animals that have experienced the same conditions, allowing for correlation analyses, which detect clusters that map to various cell types and to networks of coordinately functioning cells. A core network--expressing mRNAs including IL-1α, IL-6, IL-17A, and IL-10--expands adaptively with exposure to dryness, suppressing IFN-γ, but potentially causing physiological dysfunction. High temperature elicits concurrent increases of mRNAs for prolactin (PRL), CCL21, and IL-18. PRL is associated with crosstalk to IFN-γ, BAFF, and IL-4. The core network reacts to the resulting PRL-BAFF-IL-4 network, creating a profile reminiscent of Sjögren's disease. In a warmer, moderately dry setting, PRL-associated increases of IFN-γ are associated with suppression of IL-10 and augmentations of IL-1α and IL-17, creating a profile reminiscent of severe chronic inflammation.
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Affiliation(s)
- Austin K Mircheff
- Department of Physiology & Biophysics, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California; Department of Ophthalmology, Doheny Eye Institute, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California.
| | - Yanru Wang
- Department of Physiology & Biophysics, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California
| | - Chuanqing Ding
- Department of Pharmacology & Pharmaceutical Sciences, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California; Department of Cell & Neurobiology, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California
| | - Dwight W Warren
- Department of Cell & Neurobiology, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California
| | - Joel E Schechter
- Department of Cell & Neurobiology, Keck School of Medicine and School of Pharmacy, University of Southern California, Los Angeles, California
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Li CY, Wu SL, Sun LX, Yan TT, Wang Y. Protective Effect of Zengye Decoction () on Submandibular Glands in Nonobese Diabetic Mice. Chin J Integr Med 2014; 25:45-50. [PMID: 25253552 DOI: 10.1007/s11655-014-1981-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2014] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice. METHODS Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction. RESULTS Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05). CONCLUSIONS ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.
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Affiliation(s)
- Cheng-Yin Li
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Su-Ling Wu
- Nanjing Hospital of Traditional Chinese Medicine, Nanjing, 210001, China
| | - Li-Xia Sun
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ting-Ting Yan
- Institute for Ancient Texts of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yue Wang
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Experimental study of local inner ear gene therapy for controlling autoimmune sensorineural hearing loss. BIOMED RESEARCH INTERNATIONAL 2014; 2014:134658. [PMID: 24804196 PMCID: PMC3997895 DOI: 10.1155/2014/134658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/24/2014] [Accepted: 03/03/2014] [Indexed: 12/31/2022]
Abstract
This study aimed to investigate the efficacy of gene therapy for treating autoimmune sensorineural hearing loss (ASHL) via local administration of a recombinant adenovirus vector containing the Fas ligand or interleukin IL-10 gene. Guinea pigs were divided into four groups, with different microinjections in the scala tympani. Group A were injected with FasL-EGFP, B with IL-10-EGFP, C with EGFP, and D with artificial perilymph. Seven days later, auditory brain-stem response (ABR) was tested, and the temporal bone was stained and observed by light microscopy. The spiral ligament and basement membrane were observed using transmission electron microscopy. FasL and IL-10 expression were examined using immunofluorescence histochemistry. Immunohistochemical analysis showed that the recombinant adenovirus vector in Groups A, B, and C can transfect the stria vascularis, the spiral ligament, the organ of Corti, the spiral ganglion, the region surrounding the small blood vessel in the modiolus, and the cochlear bone wall. Compared with those in Groups C and D, the ABR wave III mean thresholds were significantly lower and the inner ear immunoinflammatory responses in Groups A and B were significantly alleviated. Inhibition of immunoinflammatory response alleviated immunoinflammatory injury and auditory dysfunction. This technique shows potential as a novel therapy for ASHL.
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Corneal gene therapy: basic science and translational perspective. Ocul Surf 2013; 11:150-64. [PMID: 23838017 DOI: 10.1016/j.jtos.2012.10.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 10/21/2012] [Accepted: 12/01/2012] [Indexed: 11/20/2022]
Abstract
Corneal blindness is the third leading cause of blindness worldwide. Gene therapy is an emerging technology for corneal blindness due to the accessibility and immune-privileged nature of the cornea, ease of vector administration and visual monitoring, and ability to perform frequent noninvasive corneal assessment. Vision restoration by gene therapy is contingent upon vector and mode of therapeutic gene introduction into targeted cells/tissues. Numerous efficacious vectors, delivery techniques, and approaches have evolved in the last decade for developing gene-based interventions for corneal diseases. Maximizing the potential benefits of gene therapy requires efficient and sustained therapeutic gene expression in target cells, low toxicity, and a high safety profile. This review describes the basic science associated with many gene therapy vectors and the present progress of gene therapy carried out for various ocular surface disorders and diseases.
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Rocha EM, Di Pasquale G, Riveros PP, Quinn K, Handelman B, Chiorini JA. Transduction, tropism, and biodistribution of AAV vectors in the lacrimal gland. Invest Ophthalmol Vis Sci 2011; 52:9567-72. [PMID: 22110082 DOI: 10.1167/iovs.11-8171] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE The lacrimal gland (LG) delivers defensive and metabolic factors to the ocular surface. These functions may be disrupted in several diseases, and for most of them there is no cure. The aim of this study is to investigate conditions and limitations for using adeno-associated virus (AAV) vectors as gene transfer agents to LG. METHODS Eight-week-old Balb/c mice were used to investigate route, gene expression, and time course of AAV gene vector transfer to LG. AAV vectors encoding firefly luciferase were administered to the LG and luciferase expression was evaluated in vivo by immunohistochemistry. Ocular surface and neutralizing antibodies were also evaluated. RESULTS The present work revealed that AAV vectors are able to delivery DNA to the LGs of mice. Direct injection had the highest level of transduction, and topical ocular drops the lowest. Overall, the AAV strain with highest transduction activity as measured by both luminescence and immunohistochemistry was AAV9, followed by AAV 5w8 and AAV5. Transduction was not different between sexes, could be detected as soon as 24 hours after injection, and lasted for at least 30 days (study termination). No tissue damage was observed when compared with controls. All vectors with detectable LG transduction induced neutralizing antibodies. CONCLUSIONS LG gene delivery by AAV vectors appears to be both safe and well tolerated. The choice of vector influences both the overall transduction activity, as well as the spread of vector to other organs. This work supports the use of AAV-mediated gene therapy for dry eye.
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Affiliation(s)
- Eduardo M Rocha
- Molecular Physiology and Therapeutic Branch, NIDCR, NIH, Bethesda, Maryland, USA.
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Mircheff AK, Wang Y, Thomas PB, Nakamura T, Samant D, Trousdale MD, Warren DW, Ding C, Schechter JE. Systematic Variations in Immune Response-Related Gene Transcript Abundance Suggest New Questions about Environmental Influences on Lacrimal Gland Immunoregulation. Curr Eye Res 2011; 36:285-94. [DOI: 10.3109/02713683.2010.550408] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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