EMBO Molecular Medicine (Apr 2022)
Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes
- 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
Affiliations
- Sophia Grotz
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Jessica Schäfer
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Kirsten A Wunderlich
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Zdenka Ellederova
- Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic
- Hannah Auch
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Andrea Bähr
- Center for Innovative Medical Models LMU Munich Munich Germany
- Petra Runa‐Vochozkova
- Large Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich Germany
- Janet Fadl
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Vanessa Arnold
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Taras Ardan
- Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic
- Miroslav Veith
- Ophthalmology Clinic University Hospital Kralovske Vinohrady Praha Czech Republic
- Gianluca Santamaria
- Large Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich Germany
- Georg Dhom
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Wolfgang Hitzl
- Biostatistics and Data Science Paracelsus Medical University Salzburg Austria
- Barbara Kessler
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Christian Eckardt
- Center for Innovative Medical Models LMU Munich Munich Germany
- Joshua Klein
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Anna Brymova
- Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic
- Joshua Linnert
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Mayuko Kurome
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Valeri Zakharchenko
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Andrea Fischer
- Veterinary Faculty Small Animal Clinics LMU Munich Munich Germany
- Andreas Blutke
- Institute of Experimental Genetics Helmholtz Center Munich Neuherberg Germany
- Anna Döring
- Veterinary Faculty Small Animal Clinics LMU Munich Munich Germany
- Stepanka Suchankova
- Institute of Experimental Medicine Czech Academy of Science Prague Czech Republic
- Jiri Popelar
- Institute of Experimental Medicine Czech Academy of Science Prague Czech Republic
- Eduardo Rodríguez‐Bocanegra
- Centre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen Germany
- Julia Dlugaiczyk
- Department of Otorhinolaryngology, Head and Neck Surgery University Hospital Zurich (USZ) University of Zurich Zurich Switzerland
- Hans Straka
- Faculty of Biology LMU Munich Planegg Germany
- Helen May‐Simera
- Institute of Molecular Physiology Cilia Biology JGU Mainz Mainz Germany
- Weiwei Wang
- Grousbeck Gene Therapy Center Mass Eye and Ear and Harvard Medical School Boston MA USA
- Karl‐Ludwig Laugwitz
- Large Animal Models in Cardiovascular Research Internal Medical Department I TU Munich Munich Germany
- Luk H Vandenberghe
- Grousbeck Gene Therapy Center Mass Eye and Ear and Harvard Medical School Boston MA USA
- Eckhard Wolf
- Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany
- Kerstin Nagel‐Wolfrum
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Tobias Peters
- Centre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen Germany
- Jan Motlik
- Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic
- M Dominik Fischer
- Oxford Eye Hospital Oxford University NHS Foundation Trust Oxford UK
- Uwe Wolfrum
- Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University (JGU) Mainz Germany
- Nikolai Klymiuk
- Center for Innovative Medical Models LMU Munich Munich Germany
- DOI
- https://doi.org/10.15252/emmm.202114817
- Journal volume & issue
-
Vol. 14,
no. 4
pp. n/a – n/a
Abstract
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.
Keywords