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

被引：24

作者：

Grotz, Sophia ^{[1
,2
]}

Schaefer, Jessica ^{[3
]}

Wunderlich, Kirsten A. ^{[3
,21
]}

Ellederova, Zdenka ^{[4
]}

Auch, Hannah ^{[1
,2
]}

Baehr, Andrea ^{[2
,5
]}

Runa-Vochozkova, Petra ^{[5
]}

Fadl, Janet ^{[1
,3
]}

Arnold, Vanessa ^{[3
]}

Ardan, Taras ^{[4
]}

Veith, Miroslav ^{[6
]}

Santamaria, Gianluca ^{[5
]}

Dhom, Georg ^{[1
,2
]}

Hitzl, Wolfgang ^{[7
]}

Kessler, Barbara ^{[1
,2
]}

Eckardt, Christian ^{[2
,5
]}

Klein, Joshua ^{[3
]}

Brymova, Anna ^{[4
]}

Linnert, Joshua ^{[3
]}

Kurome, Mayuko ^{[1
,2
]}

Zakharchenko, Valeri ^{[1
,2
]}

Fischer, Andrea ^{[8
]}

Blutke, Andreas ^{[9
]}

Doering, Anna ^{[8
]}

Suchankova, Stepanka ^{[10
]}

Popelar, Jiri ^{[10
]}

Rodriguez-Bocanegra, Eduardo ^{[11
,12
]}

Dlugaiczyk, Julia ^{[13
]}

Straka, Hans ^{[14
]}

May-Simera, Helen ^{[15
]}

Wang, Weiwei ^{[16
,17
]}

Laugwitz, Karl-Ludwig ^{[5
]}

Vandenberghe, Luk H. ^{[16
,17
]}

Wolf, Eckhard ^{[1
,2
]}

Nagel-Wolfrum, Kerstin ^{[3
,18
]}

Peters, Tobias ^{[11
,12
]}

Motlik, Jan ^{[4
]}

Fischer, M. Dominik ^{[19
,20
]}

Wolfrum, Uwe ^{[3
]}

Klymiuk, Nikolai ^{[2
,5
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Chair Mol Anim Breeding & Biotechnol, Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Ctr Innovat Med Models, Munich, Germany

[3] Johannes Gutenberg Univ OGU, Inst Mol Physiol, Mol Cell Biol, Mainz, Germany

[4] Czech Acad Sci, Inst Anim Physiol & Genet, Libechov, Czech Republic

[5] Tech Univ Munich, Internal Med Dept 1, Large Anim Models Cardiovasc Res, Munich, Germany

[6] Univ Hosp Kralovske Vinohrady, Ophthalmol Clin, Prague 6, Czech Republic

[7] Paracelsus Med Univ, Biostat & Data Sci, Salzburg, Austria

[8] Ludwig Maximilians Univ Munchen, Small Anim Clin, Vet Fac, Munich, Germany

[9] Helmholtz Ctr Munich, Inst Expt Genet, Neuherberg, Germany

[10] Czech Acad Sci, Inst Expt Med, Prague, Czech Republic

[11] Univ Eye Hosp, Univ Hosp Tubingen, Tubingen, Germany

[12] Univ Hosp Tubingen, Ctr Ophthalmol, Inst Ophthalm Res, Tubingen, Germany

[13] Univ Zurich, Univ Hosp Zurich USZ, Dept Otorhinolaryngol Head & Neck Surg, Zurich, Switzerland

[14] Ludwig Maximilians Univ Munchen, Fac Biol, Planegg, Germany

[15] JGU Mainz, Inst Mol Physiol, Cilia Biol, Mainz, Germany

[16] Mass Eye & Ear, Grousbeck Gene Therapy Ctr, Boston, MA USA

[17] Harvard Med Sch, Boston, MA 02115 USA

[18] Johannes Gutenberg Univ OGU, Inst Dev Biol & Neurobiol, Mainz, Germany

[19] Oxford Univ NHS Fdn Trust, Oxford, England

[20] Univ Oxford, Nuffield Lab Ophthalmol, NDCN, Oxford, England

[21] Ludwig Maximilians Univ Munchen, Dept Physiol Genom, Munich, Germany

来源：

EMBO MOLECULAR MEDICINE | 2022年 / 14卷 / 04期

关键词：

gene therapy; impaired vision; photoreceptor morphology; pig model; Usher syndrome; LARGE ANIMAL-MODEL; RETINAL DEGENERATION; SYNDROME TYPE-1; HAIR BUNDLE; MYOSIN VIIA; MOUSE; HARMONIN; PROTEIN; GENE; USH1C;

D O I：

10.15252/emmm.202114817

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：24

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