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Grotz, S.* ; Schäfer, J.* ; Wunderlich, K.A.* ; Ellederova, Z.* ; Auch, H.* ; Bähr, A.* ; Runa-Vochozkova, P.* ; Fadl, J.* ; Arnold, V.* ; Ardan, T.* ; Veith, M.* ; Santamaria, G.* ; Dhom, G.* ; Hitzl, W.* ; Kessler, B.* ; Eckardt, C.* ; Klein, J.* ; Brymova, A.* ; Linnert, J.* ; Kurome, M.* ; Zakharchenko, V.* ; Fischer, A.* ; Blutke, A. ; Döring, A.* ; Suchankova, S.* ; Popelar, J.* ; Rodríguez-Bocanegra, E.* ; Dlugaiczyk, J.* ; Straka, H.* ; May-Simera, H.* ; Wang, W.* ; Laugwitz, K.L.* ; Vandenberghe, L.H.* ; Wolf, E.* ; Nagel-Wolfrum, K.* ; Peters, T.* ; Motlik, J.* ; Fischer, M.D.* ; Wolfrum, U.* ; Klymiuk, N.*

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes.

EMBO Mol. Med.:e14817 (2022)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Usher Syndrome ; Gene Therapy ; Impaired Vision ; Photoreceptor Morphology ; Pig Model; Large Animal-model; Retinal Degeneration; Syndrome Type-1; Hair Bundle; Myosin Viia; Mouse; Harmonin; Protein; Gene; Ush1c

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Article Number: e14817

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)

Grants FAUN Stiftung
Foundation Fighting Blindness
USHER2020
Deutsche Forschungsgemeinschaft (DFG)