TY - JOUR
T1 - Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes
AU - Grotz, Sophia
AU - Schäfer, Jessica
AU - Wunderlich, Kirsten A.
AU - Ellederova, Zdenka
AU - Auch, Hannah
AU - Bähr, Andrea
AU - Runa-Vochozkova, Petra
AU - Fadl, Janet
AU - Arnold, Vanessa
AU - Ardan, Taras
AU - Veith, Miroslav
AU - Santamaria, Gianluca
AU - Dhom, Georg
AU - Hitzl, Wolfgang
AU - Kessler, Barbara
AU - Eckardt, Christian
AU - Klein, Joshua
AU - Brymova, Anna
AU - Linnert, Joshua
AU - Kurome, Mayuko
AU - Zakharchenko, Valeri
AU - Fischer, Andrea
AU - Blutke, Andreas
AU - Döring, Anna
AU - Suchankova, Stepanka
AU - Popelar, Jiri
AU - Rodríguez-Bocanegra, Eduardo
AU - Dlugaiczyk, Julia
AU - Straka, Hans
AU - May-Simera, Helen
AU - Wang, Weiwei
AU - Laugwitz, Karl Ludwig
AU - Vandenberghe, Luk H.
AU - Wolf, Eckhard
AU - Nagel-Wolfrum, Kerstin
AU - Peters, Tobias
AU - Motlik, Jan
AU - Fischer, M. Dominik
AU - Wolfrum, Uwe
AU - Klymiuk, Nikolai
N1 - Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022/4/7
Y1 - 2022/4/7
N2 - 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.
AB - 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.
KW - Usher syndrome
KW - gene therapy
KW - impaired vision
KW - photoreceptor morphology
KW - pig model
UR - http://www.scopus.com/inward/record.url?scp=85125669882&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114817
DO - 10.15252/emmm.202114817
M3 - Article
C2 - 35254721
AN - SCOPUS:85125669882
SN - 1757-4676
VL - 14
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e14817
ER -