Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy
There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/981 |
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| author | Shravan K. Chintala Jinhong Pan Sandeep Satapathy Rebecca Condruti Zixuan Hao Pei-wen Liu Christian F. O’Conner Joseph T. Barr Mark R. Wilson Shinwu Jeong M. Elizabeth Fini |
| author_facet | Shravan K. Chintala Jinhong Pan Sandeep Satapathy Rebecca Condruti Zixuan Hao Pei-wen Liu Christian F. O’Conner Joseph T. Barr Mark R. Wilson Shinwu Jeong M. Elizabeth Fini |
| author_sort | Shravan K. Chintala |
| collection | DOAJ |
| description | There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases. |
| first_indexed | 2024-03-09T12:27:11Z |
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| id | doaj.art-d88af29079c949d3ab661a3d7f3131be |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:27:11Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d88af29079c949d3ab661a3d7f3131be2023-11-30T22:33:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-0124298110.3390/ijms24020981Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced EpitheliopathyShravan K. Chintala0Jinhong Pan1Sandeep Satapathy2Rebecca Condruti3Zixuan Hao4Pei-wen Liu5Christian F. O’Conner6Joseph T. Barr7Mark R. Wilson8Shinwu Jeong9M. Elizabeth Fini10USC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USANew England Eye Center, Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USASchool of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW 2522, AustraliaTraining Program in Cell, Molecular and Developmental Biology, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USATraining Program in Pharmacology and Drug Development, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USATraining Program in Pharmacology and Drug Development, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USADoctor of Medicine Training Program, Tufts University School of Medicine, Boston, MA 02111, USAThe Ohio State University College of Optometry, Columbus, OH 43210, USASchool of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong, NSW 2522, AustraliaUSC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USANew England Eye Center, Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USAThere is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.https://www.mdpi.com/1422-0067/24/2/981clusterindry eyeocular surfaceepitheliopathymolecular chaperonematrix metalloproteinase inhibitor |
| spellingShingle | Shravan K. Chintala Jinhong Pan Sandeep Satapathy Rebecca Condruti Zixuan Hao Pei-wen Liu Christian F. O’Conner Joseph T. Barr Mark R. Wilson Shinwu Jeong M. Elizabeth Fini Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy International Journal of Molecular Sciences clusterin dry eye ocular surface epitheliopathy molecular chaperone matrix metalloproteinase inhibitor |
| title | Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy |
| title_full | Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy |
| title_fullStr | Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy |
| title_full_unstemmed | Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy |
| title_short | Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy |
| title_sort | recombinant human clusterin seals damage to the ocular surface barrier in a mouse model of ophthalmic preservative induced epitheliopathy |
| topic | clusterin dry eye ocular surface epitheliopathy molecular chaperone matrix metalloproteinase inhibitor |
| url | https://www.mdpi.com/1422-0067/24/2/981 |
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