Open AccessEarly disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes
Author(s) -
Grotz Sophia,
Schäfer Jessica,
Wunderlich Kirsten A,
Ellederova Zdenka,
Auch Hannah,
Bähr Andrea,
RunaVochozkova Petra,
Fadl Janet,
Arnold Vanessa,
Ardan Taras,
Veith Miroslav,
Santamaria Gianluca,
Dhom Georg,
Hitzl Wolfgang,
Kessler Barbara,
Eckardt Christian,
Klein Joshua,
Brymova Anna,
Linnert Joshua,
Kurome Mayuko,
Zakharchenko Valeri,
Fischer Andrea,
Blutke Andreas,
Döring Anna,
Suchankova Stepanka,
Popelar Jiri,
RodríguezBocanegra Eduardo,
Dlugaiczyk Julia,
Straka Hans,
MaySimera Helen,
Wang Weiwei,
Laugwitz KarlLudwig,
Vandenberghe Luk H,
Wolf Eckhard,
NagelWolfrum Kerstin,
Peters Tobias,
Motlik Jan,
Fischer M Dominik,
Wolfrum Uwe,
Klymiuk Nikolai
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114817
Subject(s) - usher syndrome , cilium , retinal degeneration , medicine , blindness , biology , microbiology and biotechnology , ophthalmology , retinal , retinitis pigmentosa , optometry
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 .