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.

Biostatistics and Data Science Paracelsus Medical University Salzburg Austria

Center for Innovative Medical Models LMU Munich Munich Germany

Centre for Ophthalmology University Eye Hospital University Hospital Tübingen Tübingen Germany

Chair of Molecular Animal Breeding and Biotechnology LMU Munich Munich Germany

Department of Otorhinolaryngology Head and Neck Surgery University Hospital Zurich University of Zurich Zurich Switzerland

Faculty of Biology LMU Munich Planegg Germany

Grousbeck Gene Therapy Center Mass Eye and Ear and Harvard Medical School Boston MA USA

Institute for Ophthalmic Research Centre for Ophthalmology University Hospital Tübingen Tübingen Germany

Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic

Institute of Developmental Biology and Neurobiology Johannes Gutenberg University Mainz Germany

Institute of Experimental Genetics Helmholtz Center Munich Neuherberg Germany

Institute of Experimental Medicine Czech Academy of Science Prague Czech Republic

Institute of Molecular Physiology Cilia Biology JGU Mainz Mainz Germany

Institute of Molecular Physiology Molecular Cell Biology Johannes Gutenberg University Mainz Germany

Large Animal Models in Cardiovascular Research Internal Medical Department 1 TU Munich Munich Germany

Nuffield Laboratory of Ophthalmology NDCN University of Oxford Oxford UK

Ophthalmology Clinic University Hospital Kralovske Vinohrady Praha Czech Republic

Oxford Eye Hospital Oxford University NHS Foundation Trust Oxford UK

Veterinary Faculty Small Animal Clinics LMU Munich Munich Germany

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