Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes
Abstract Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene...
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| Language: | English |
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Springer Nature
2022-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114817 |
| _version_ | 1797285502747934720 |
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| author | Sophia Grotz Jessica Schäfer Kirsten A Wunderlich Zdenka Ellederova Hannah Auch Andrea Bähr Petra Runa‐Vochozkova Janet Fadl Vanessa Arnold Taras Ardan Miroslav Veith Gianluca Santamaria Georg Dhom Wolfgang Hitzl Barbara Kessler Christian Eckardt Joshua Klein Anna Brymova Joshua Linnert Mayuko Kurome Valeri Zakharchenko Andrea Fischer Andreas Blutke Anna Döring Stepanka Suchankova Jiri Popelar Eduardo Rodríguez‐Bocanegra Julia Dlugaiczyk Hans Straka Helen May‐Simera Weiwei Wang Karl‐Ludwig Laugwitz Luk H Vandenberghe Eckhard Wolf Kerstin Nagel‐Wolfrum Tobias Peters Jan Motlik M Dominik Fischer Uwe Wolfrum Nikolai Klymiuk |
| author_facet | Sophia Grotz Jessica Schäfer Kirsten A Wunderlich Zdenka Ellederova Hannah Auch Andrea Bähr Petra Runa‐Vochozkova Janet Fadl Vanessa Arnold Taras Ardan Miroslav Veith Gianluca Santamaria Georg Dhom Wolfgang Hitzl Barbara Kessler Christian Eckardt Joshua Klein Anna Brymova Joshua Linnert Mayuko Kurome Valeri Zakharchenko Andrea Fischer Andreas Blutke Anna Döring Stepanka Suchankova Jiri Popelar Eduardo Rodríguez‐Bocanegra Julia Dlugaiczyk Hans Straka Helen May‐Simera Weiwei Wang Karl‐Ludwig Laugwitz Luk H Vandenberghe Eckhard Wolf Kerstin Nagel‐Wolfrum Tobias Peters Jan Motlik M Dominik Fischer Uwe Wolfrum Nikolai Klymiuk |
| author_sort | Sophia Grotz |
| collection | DOAJ |
| description | Abstract Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas‐mediated gene repair or gene therapy in vitro. AAV‐based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo. |
| first_indexed | 2024-03-07T18:04:06Z |
| format | Article |
| id | doaj.art-f0ba22f95e7b4b36b03173d767e7f90f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:04:06Z |
| publishDate | 2022-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-f0ba22f95e7b4b36b03173d767e7f90f2024-03-02T10:17:44ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-04-01144n/an/a10.15252/emmm.202114817Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromesSophia Grotz0Jessica Schäfer1Kirsten A Wunderlich2Zdenka Ellederova3Hannah Auch4Andrea Bähr5Petra Runa‐Vochozkova6Janet Fadl7Vanessa Arnold8Taras Ardan9Miroslav Veith10Gianluca Santamaria11Georg Dhom12Wolfgang Hitzl13Barbara Kessler14Christian Eckardt15Joshua Klein16Anna Brymova17Joshua Linnert18Mayuko Kurome19Valeri Zakharchenko20Andrea Fischer21Andreas Blutke22Anna Döring23Stepanka Suchankova24Jiri Popelar25Eduardo Rodríguez‐Bocanegra26Julia Dlugaiczyk27Hans Straka28Helen May‐Simera29Weiwei Wang30Karl‐Ludwig Laugwitz31Luk H Vandenberghe32Eckhard Wolf33Kerstin Nagel‐Wolfrum34Tobias Peters35Jan Motlik36M Dominik Fischer37Uwe Wolfrum38Nikolai Klymiuk39Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyInstitute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech RepublicChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyCenter for Innovative Medical Models LMU Munich Munich GermanyLarge Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich GermanyChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyInstitute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech RepublicOphthalmology Clinic University Hospital Kralovske Vinohrady Praha Czech RepublicLarge Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich GermanyChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyBiostatistics and Data Science Paracelsus Medical University Salzburg AustriaChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyCenter for Innovative Medical Models LMU Munich Munich GermanyInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyInstitute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech RepublicInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyVeterinary Faculty Small Animal Clinics LMU Munich Munich GermanyInstitute of Experimental Genetics Helmholtz Center Munich Neuherberg GermanyVeterinary Faculty Small Animal Clinics LMU Munich Munich GermanyInstitute of Experimental Medicine Czech Academy of Science Prague Czech RepublicInstitute of Experimental Medicine Czech Academy of Science Prague Czech RepublicCentre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery University Hospital Zurich (USZ) University of Zurich Zurich SwitzerlandFaculty of Biology LMU Munich Planegg GermanyInstitute of Molecular Physiology Cilia Biology JGU Mainz Mainz GermanyGrousbeck Gene Therapy Center Mass Eye and Ear and Harvard Medical School Boston MA USALarge Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich GermanyGrousbeck Gene Therapy Center Mass Eye and Ear and Harvard Medical School Boston MA USAChair of Molecular Animal Breeding and Biotechnology LMU Munich Munich GermanyInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyCentre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen GermanyInstitute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech RepublicOxford Eye Hospital Oxford University NHS Foundation Trust Oxford UKInstitute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz GermanyCenter for Innovative Medical Models LMU Munich Munich GermanyAbstract Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas‐mediated gene repair or gene therapy in vitro. AAV‐based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.https://doi.org/10.15252/emmm.202114817gene therapyimpaired visionphotoreceptor morphologypig modelUsher syndrome |
| spellingShingle | Sophia Grotz Jessica Schäfer Kirsten A Wunderlich Zdenka Ellederova Hannah Auch Andrea Bähr Petra Runa‐Vochozkova Janet Fadl Vanessa Arnold Taras Ardan Miroslav Veith Gianluca Santamaria Georg Dhom Wolfgang Hitzl Barbara Kessler Christian Eckardt Joshua Klein Anna Brymova Joshua Linnert Mayuko Kurome Valeri Zakharchenko Andrea Fischer Andreas Blutke Anna Döring Stepanka Suchankova Jiri Popelar Eduardo Rodríguez‐Bocanegra Julia Dlugaiczyk Hans Straka Helen May‐Simera Weiwei Wang Karl‐Ludwig Laugwitz Luk H Vandenberghe Eckhard Wolf Kerstin Nagel‐Wolfrum Tobias Peters Jan Motlik M Dominik Fischer Uwe Wolfrum Nikolai Klymiuk Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes EMBO Molecular Medicine gene therapy impaired vision photoreceptor morphology pig model Usher syndrome |
| title | Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| title_full | Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| title_fullStr | Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| title_full_unstemmed | Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| title_short | Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| title_sort | early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes |
| topic | gene therapy impaired vision photoreceptor morphology pig model Usher syndrome |
| url | https://doi.org/10.15252/emmm.202114817 |
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